4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds

ABSTRACT

This invention relates to novel phenyl amide or pyridyl amide derivatives of the formula 
     
       
         
         
             
             
         
       
     
     wherein A 1 , A 2 , B 1 , B 2  and R 1  to R 11  are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are GPBAR 1  agonists and can be used as medicaments for the treatment of diseases such as type II diabetes.

PRIORITY TO RELATED APPLICATION(S)

This application is a continuation application of U.S. Ser. No.13/005,566, filed Jan. 13, 2011, and claims the benefit of EuropeanPatent Application No. 10151319.0, filed Jan. 21, 2010, which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel 4-phenoxy-nicotinamide or4-phenoxy-pyrimidine-5-carboxamide derivatives, their manufacture,pharmaceutical compositions containing them and their use asmedicaments.

The compounds of formula I possess pharmaceutical activity, inparticular they are modulators or ligands of the GPBAR1 receptor. Moreparticularly, the compounds are potent GPBAR1 agonists.

BACKGROUND OF THE INVENTION

Diabetes mellitus is an ever-increasing threat to human health. Forexample, in the United States current estimates maintain that about 16million people suffer from diabetes mellitus. Type II diabetes alsoknown as non-insulin-dependent diabetes mellitus accounts forapproximately 90-95% of diabetes cases, killing about 193,000 U.S.residents each year. Type II diabetes is the seventh leading cause ofall deaths. In Western societies, type II diabetes currently affects 6%of the adult population with world-wide frequency expected to grow by 6%per annum. Although there are certain inheritable traits that maypredispose particular individuals to developing type II diabetes, thedriving force behind the current increase in incidence of the disease isthe increased sedentary life-style, diet, and obesity now prevalent indeveloped countries. About 80% of diabetics with type II diabetes aresignificantly overweight. Also, an increasing number of young people aredeveloping the disease. Type II diabetes is now internationallyrecognized as one of the major threats to human health in the 21stcentury.

Type II diabetes manifests as inability to adequately regulateblood-glucose levels and may be characterized by a defect in insulinsecretion or by insulin resistance. Namely, those who suffer from TypeII diabetes have too little insulin or cannot use insulin effectively.Insulin resistance refers to the inability of the body tissues torespond properly to endogenous insulin. Insulin resistance developsbecause of multiple factors, including genetics, obesity, increasingage, and having high blood sugar over long periods of time. Type IIdiabetes, sometimes called mature on set, can develop at any age, butmost commonly becomes apparent during adulthood. However, the incidenceof type II diabetes in children is rising. In diabetics glucose levelsbuild up in the blood and urine causing excessive urination, thirst,hunger, and problems with fat and protein metabolism. If left untreated,diabetes mellitus may cause life-threatening complications, includingblindness, kidney failure, and heart disease.

Type II diabetes is currently treated at several levels. A first levelof therapy is through diet and/or exercise, either alone or incombination with therapeutic agents. Such agents may include insulin orpharmaceuticals that lower blood glucose levels. About 49% ofindividuals with Type II diabetes require oral medications, about 40%require insulin injections or a combination of insulin injections andoral medications, and 10% use diet and exercise alone.

Current therapies include: insulin secretagogues, such assulphonylureas, which increase insulin production from pancreaticβ-cells; glucose-lowering effectors, such as metformin which reduceglucose production from the liver; activators of the peroxisomeproliferator-activated receptor γ (PPARγ), such as thethiazolidinediones, which enhances insulin action; and α-glucosidaseinhibitors which interfere with gut glucose production. There are,however, deficiencies associated with currently available treatments.For example sulphonylureas and insulin injections can be associated withhypoglycemic episodes and weight gain. Furthermore, patients often loseresponsiveness to sulphonylureas over time. Metformin and α-glucosidaseinhibitors often lead to gastrointestinal problems and PPARy agoniststend to cause increased weight gain and edema.

Bile acids (BA) are amphipathic molecules which are synthesized in theliver from cholesterol and stored in the gall bladder until secretion tothe duodenum and intestine to play an important role in thesolubilization and absorption of dietary fat and lipid-soluble vitamins.Approx. 99% of BA are absorbed again by passive diffusion and activetransport in the terminal ileum and transported back to the liver viathe portal vein (enterohepatic circulation). In the liver, BA decreasetheir own biosynthesis from cholesterol through the activation of thefarnesoid X receptor alpha (FXRα) and small heterodimer partner (SHP),leading to the transcriptional repression of cholesterol 7α-hydroxylase,the rate-limiting step of BA biosynthesis from cholesterol.

GPBAR1, in the literature termed TGR5, M-BAR or BG37 as well, wasrecently identified as a G-protein coupled receptor (GPCR) responsive toBA (Kawamata et al., J. Biol. Chem. 2003, 278, 9435-9440; Maruyama etal., Biochem. Biophys. Res. Commun. 2002, 298, 714-719). GPBAR1 is aG(alpha)s-coupled GPCR and stimulation by ligand binding causesactivation of adenylyl cyclase which leads to the elevation ofintracellular cAMP and subsequent activation of downstream signalingpathways. The human receptor shares 86, 90, 82, and 83% amino acididentity to bovine, rabbit, rat, and mouse receptor, respectively.GPBAR1 is abundantly expressed in the intestinal tract, monocytes andmacrophages, lung, spleen, placenta (Kawamata et al., J. Biol. Chem.2003, 278, 9435-9440). BA induced receptor internalization,intracellular cAMP production and activation of extracellularsignal-regulated kinase in GPBAR1-expressing HEK293 and CHO cells.

GPBAR1 was found to be abundantly expressed in monocytes/macrophagesfrom humans and rabbits (Kawamata et al., J. Biol. Chem. 2003, 278,9435-9440), and BA treatment suppressed LPS-induced cytokine productionin rabbit alveolar macrophages and human THP-1 cells expressing GPBAR1.These data suggest that bile acids can suppress the macrophage functionvia activation of GPBAR1. In the liver functional GPBAR1 was found inthe plasma membranes of Kupffer cells, mediating inhibition ofLPS-induced cytokine expression (Keitel, Biochem. Biophys. Res. Commun.2008, 372, 78-84), and of sinusoidal endothelial cells, where bile saltsled to an increase in intracellular cAMP and to the activation andenhanced expression of the endothelial nitric oxide (NO) synthase(Keitel, Hepatology 2007, 45, 695-704). Furthermore, GPBAR1 has beendetected in cholangiocytes of rat liver (Keitel, Biochem. Biophys. Res.Commun. 2008, 372, 78-84). Hydrophobic bile acids, such astaurolithocholic acid, increase cAMP in cholangiocytes suggesting thatGPBAR1 may modulate ductal secretion and bile flow. Indeed, GPBAR1staining colocalized with the cyclic adenosine monophosphate regulatedchloride channel cystic fibrosis transmembrane conductance regulator(CFTR) and the apical sodium-dependent bile salt uptake transporter(ASBT). A functional coupling of GPBAR1 to chloride secretion and bileflow has been shown using GPBAR1 agonists (Keitel et al., Hepatology2009 50, 861-870; Pellicciari et al., J Med Chem 2009, 52(24),7958-7961). In summary, GPBAR1 agonists may trigger a protective as wellas medicative mechanism in cholestatic livers.

GPBAR1 is expressed in intestinal enteroendocrine cell lines from human(NCI-H716) and murine (STC-1, GLUTag) origin (Maruyama et al., Biochem.Biophys. Res. Commun. 2002, 298, 714-719). Stimulation of GPBAR1 by BAstimulated cAMP production in NCI-H716 cells. Intracellular increases incAMP suggested that BA may induce the secretion of glucagon-likepeptide-1 (GLP-1). Indeed, activation of GPBAR1 by BA promoted GLP-1secretion in STC-1 cells (Katsuma et al., Biochem. Biophys. Res. Commun.2005, 329, 386-390). Receptor-specificity has been demonstrated by RNAinterference experiments which revealed that reduced expression ofGPBAR1 resulted in diminished secretion of GLP-1. There is compellingevidence that GPBAR1-mediated GLP-1 and PYY release from intestinalL-cells extends to in vivo. In the isolated vascularly perfused ratcolon, BAs have been shown to trigger GLP-1 secretion (Plaisancie etal., J. Endocrin. 1995, 145, 521-526). Using a combination ofpharmacological and genetic gain- and loss-of-function studies in vivo,GPBAR1 signaling was shown to induce GLP-1 release, leading to improvedliver and pancreatic function and enhanced glucose tolerance in obesemice (Thomas et al., Cell Metabolism, 2009, 10, 167-177). In humans,intracolonic administration of deoxycholate showed marked increases inplasma levels of GLP-1 and the co-secreted PYY (Adrian et al., Gut 1993,34, 1219-1224).

GLP-1 is a peptide secreted from enteroendocrine L cells has been shownto stimulate insulin release in glucose dependent manner in humans(Kreymann et al., Lancet 1987, 2, 1300-1304) and studies in experimentalanimals demonstrated that this incretin hormone is necessary for normalglucose homeostasis. In addition, GLP-1 can exert several beneficialeffects in diabetes and obesity, including 1) increased glucosedisposal, 2) suppression in glucose production, 3) reduced gastricemptying, 4) reduction in food intake and 5) weight loss. More recently,much research has been focused on the use of GLP-1 in the treatment ofconditions and disorders such as diabetes mellitus, stress, obesity,appetite control and satiety, Alzheimer disease, inflammation, anddiseases of the central nervous system. (See, for example, Bojanowska etal., Med. Sci. Monit. 2005, 8, RA271-8; Perry et al., Current AlzheimerRes. 2005, 3, 377-385; and Meier et al., Diabetes Metab. Res. Rev. 2005,2, 91-117). However, the use of a peptide in clinical treatment islimited due to difficult administration, and in vivo stability.Therefore, a small molecule that either mimics the effects of GLP-1directly, or increases GLP-1 secretion, may be useful in treatment ofthe variety of conditions or disorders described above, namely diabetesmellitus.

PYY is co-secreted with GLP-1 from intestinal L-cells following a meal.A dipeptidyl peptidase-IV (DPP4) cleavage product of PYY is PYY[3-36](Eberlein et al. Peptides 1989, 10, 797-803) (Grandt et al. Regul Pept1994, 51, 151-159). This fragment constitutes approximately 40% of totalPYY-like immunoreactivity in human and canine intestinal extracts andabout 36% of total plasma PYY immunoreactivity in a fasting state toslightly over 50% following a meal. PYY[3-36] is reportedly a selectiveligand at the Y2 and Y5 receptors. Peripheral administration of PYYreportedly reduces gastric acid secretion, gastric motility, exocrinepancreatic secretion (Yoshinaga et al. Am J Physiol 1992, 263,G695-701), gallbladder contraction and intestinal motility (Savage etal. Gut 1987, 28, 166-170). It has been demonstrated that Intra-arcuate(IC) or Intra-peritoneal (IP) injection of PYY3-36 reduced feeding inrats and, as a chronic treatment, reduced body weight gain. Intra-venous(IV) infusion (0.8 pmol/kg/min) for 90 min of PYY3-36 reduced foodintake in obese and normal human subjects 33% over 24 hours. Thesefinding suggest that the PYY system may be a therapeutic target for thetreatment of obesity (Bloom et. al. Nature 2002, 418, 650-654).

Furthermore, activation of GPBAR1 might be beneficial for the treatmentof obesity and metabolic syndrome. Mice fed a high fat diet (HFD)containing 0.5% cholic acid gained less weight than control mice on HFDalone independent of food intake (Watanabe et al., Nature 2006, 439,484-489). These effects were independent of FXR-alpha, and are likely toresults from the binding of BA to GPBAR1. The proposed GPBAR1-mediatedmechanism is leading to the subsequent induction of the cAMP-dependentthyroid hormone activating enzyme type 2 (D2) which converts theinactive T3 into the active T4, resulting in the stimulation of thethyroid hormone receptor and promoting energy expenditure. Mice lackingthe D2 gene were resistant to cholic acid-induced weight loss. In bothrodents and humans, the most thermogenically important tissues (thebrown adipose and skeletal muscle) are specifically targeted by thismechanism because they co-express D2 and GPBAR1. The BA-GPBAR1-cAMP-D2signalling pathway is therefore a crucial mechanism for fine-tuningenergy homeostasis that can be targeted to improve metabolic control.

It is therefore an object of the present invention to provide selective,directly acting GPBAR1 agonists. Such agonists are useful astherapeutically active substances, particularly in the treatment and/orprevention of diseases which are associated with the activation ofGPBAR1.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I,

wherein

-   A¹ is CR¹³ or N;-   A² is CR¹⁴ or N;-   R¹ and R² are independently from each other selected from the group    consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl,    cyano and C₁₋₇-alkoxy;-   R¹³ and R¹⁴ are independently from each other selected from the    group consisting of hydrogen, C₁₋₇-alkyl, halogen,    halogen-C₁₋₇-alkyl, cyano, C₁₋₇-alkoxy, amino and    C₁₋₇-alkylsulfanyl;-   R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy, cyano, C₃₋₇-cycloalkyl,    N-heterocyclyl, five-membered heteroaryl, phenyl and NR¹⁵R¹⁶,    wherein R¹⁵ and R¹⁶ independently from each other are selected from    hydrogen, C₁₋₇-alkyl and C₃₋₇-cycloalkyl;-   R⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen-C₁₋₇-alkyl and C₃₋₇-cycloalkyl; or-   R³ and R⁴ or R³ and R¹⁴ together are X—(CR¹⁷R¹⁸)_(n)— and form part    of a ring; wherein    -   X is selected from the group consisting of —CR¹⁹R²⁰—, O, S, C═O        and NR²¹;    -   R¹⁷ and R¹⁸ are independently from each other hydrogen or        C₁₋₇-alkyl;    -   R¹⁹ and R²⁰ are independently from each other selected from the        group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl,        and heterocyclyl optionally substituted by one or two groups        selected from C₁₋₇-alkyl and halogen,    -   or R¹⁹ and R²⁰ together with the C atom they are attached to        form a cyclopropyl or oxetanyl ring or together form a ═CH₂ or        ═CF₂ group;    -   R²¹ is selected from the group consisting of hydrogen,        C₁₋₇-alkyl, halogen-C₁₋₇-alkyl, C₃₋₇-cycloalkyl optionally        substituted by carboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl,        C₃₋₇-cycloalkyl-C₁₋₇-alkyl wherein the C₃₋₇-cycloalkyl is        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl, heterocyclyl, heterocyclyl-C₁₋₇-alkyl,        heteroaryl, heteroaryl-C₁₋₇-alkyl, carboxyl-C₁₋₇-alkyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,        C₁₋₇-alkylcarbonyloxy-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl, phenyl        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl, phenylcarbonyl wherein the phenyl is        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl, and phenylsulfonyl wherein the phenyl is        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl,-   or R²¹ and a R¹⁷ together are (CH₂)₃— and form part of a ring, or    -   R²¹ together with a pair of R¹⁷ and R¹⁸ are CH═CH—CH═ and form        part of a ring;-   and n is 1, 2 or 3;-   B¹ is N or N⁺—O⁻;-   B² is CR⁷ or N;-   R⁵, R⁶ and R⁷ independently from each other are selected from the    group consisting of hydrogen, halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy,    halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, and cyano;-   and R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independently from each other    selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₂₋₇-alkenyl, C₂₋₇-alkinyl, halogen, halogen-C₁₋₇-alkyl,    C₁₋₇-alkoxy, halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkoxy,    hydroxy-C₁₋₇-alkyl, hydroxy-C₃₋₇-alkenyl, hydroxy-C₃₋₇-alkinyl,    cyano, carboxyl, C₁₋₇-alkoxycarbonyl, aminocarbonyl,    carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl, carboxyl-C₂₋₇-alkinyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkoxycarbonyl-C₂₋₇-alkinyl, carboxyl-C₁₋₇-alkoxy,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy, carboxyl-C₁₋₇-alkyl-aminocarbonyl,    carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,    carboxyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,    carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,    hydroxy-C₁₋₇-alkyl-aminocarbonyl,    di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,    aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,    hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,    hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,    di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl, phenyl    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl or C₁₋₇-alkoxycarbonyl, phenyl-carbonyl    wherein the phenyl is optionally substituted by one to three groups    selected from halogen, C₁₋₇-alkoxy, carboxyl and    C₁₋₇-alkoxycarbonyl, phenyl-aminocarbonyl wherein the phenyl is    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-C₁₋₇-alkyl    wherein the phenyl is optionally substituted by one to three groups    selected from halogen, C₁₋₇-alkoxy, carboxyl and    C₁₋₇-alkoxycarbonyl, phenyl-C₂₋₇-alkinyl wherein the phenyl is    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl optionally    substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-carbonyl    wherein the heteroaryl is optionally substituted by one to three    groups selected from halogen, C₁₋₇-alkoxy, carboxyl and    C₁₋₇-alkoxycarbonyl, heteroaryl-aminocarbonyl wherein the heteroaryl    is optionally substituted by one to three groups selected from    halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,    heteroaryl-C₁₋₇-alkyl wherein the heteroaryl is optionally    substituted by one to three groups selected from halogen,    C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,    heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein the heteroaryl is    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, and    heteroaryl-carbonyl-C₁₋₇-alkyl wherein the heteroaryl is optionally    substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl;    or a pharmaceutically acceptable salt thereof.

The present invention also provides a composition comprising a compoundas described above, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention exceed the compounds knownin the art, inasmuch as they are small molecules and they bind to andselectively activate GPBAR1 very efficiently. They are expected to havean enhanced therapeutic potential compared to the compounds alreadyknown in the art and can be used for the treatment of diabetes, obesity,metabolic syndrome, hypercholesterolemia, dyslipidemia and a wide rangeof acute and chronic inflammatory diseases.

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred, and with fluorineand chlorine being more preferred.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms. The term “C₁₋₁₀-alkyl”refers to a branched or straight-chain monovalent saturated aliphatichydrocarbon radical of one to ten carbon atoms, such as e.g., methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,1,1,3,3-tetramethyl-butyl and the like. Lower alkyl groups as describedbelow are also preferred alkyl groups.

The term “lower alkyl” or “C₁₋₇-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 7carbon atoms, preferably a straight or branched-chain alkyl group with 1to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms. Examples ofstraight-chain and branched C₁₋₇ alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, theisomeric hexyls and the isomeric heptyls, preferably methyl and ethyland most preferred methyl.

The term “lower alkenyl” or “C₂₋₇-alkenyl” signifies a straight-chain orbranched chain hydrocarbon residue comprising an olefinic bond and 2 to7, preferably 3 to 6, particularly preferred 3 to 4 carbon atoms.Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl,isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferredexample is 2-propenyl (allyl).

The term “lower alkinyl” or “C₂₋₇-alkinyl” signifies a straight-chain orbranched chain hydrocarbon residue comprising a triple bond and 2 to 7,preferably 3 to 7, particularly preferred 3 to 4 carbon atoms. Preferredalkinyl groups are ethinyl and 1-propinyl (—C≡C—CH₂).

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” denotes a saturatedcarbocyclic group containing from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.Especially preferred is cyclopropyl.

The term “lower cycloalkylalkyl” or “C₃₋₇-cycloalkyl-C₁₋₇-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by a cycloalkylgroup. Among the preferred lower cycloalkylalkyl groups residescyclopropylmethyl.

The term “lower alkoxy” or “C₁₋₇-alkoxy” refers to the group R′—O—,wherein R′ is lower alkyl and the term “lower alkyl” has the previouslygiven significance. Examples of lower alkoxy groups are methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy andtert.-butoxy, preferably methoxy.

The term “lower alkylsulfanyl” or “C₁₋₇-alkylsulfanyl” defines the group—S—R, wherein R is lower alkyl and the term “lower alkyl” has thepreviously given meaning. Examples of lower alkylsulfonyl groups aremethylsulfanyl (—SCH₃) or ethylsulfanyl (—SC₂H₅).

The term “lower alkoxycarbonyl” or “C₁₋₇-alkoxycarbonyl” refers to thegroup CO—OR′ wherein R′ is lower alkyl and the term “lower alkyl” hasthe previously given significance. Preferred lower alkoxycarbonyl groupsare methoxycarbonyl or ethoxycarbonyl.

The term “lower alkoxycarbonylalkyl” or “C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl”means lower alkyl groups as defined above wherein one of the hydrogenatoms of the lower alkyl group is replaced by C₁₋₇-alkoxycarbonyl. Apreferred lower alkoxycarbonylalkyl group is —CH₂—COOCH₃.

The term “lower alkoxycarbonylalkenyl” or“C₁₋₇-alkoxycarbonyl-C₃₋₇-alkenyl” refers to lower alkenyl groups asdefined above but having at least 3 carbon atoms wherein at least one ofthe hydrogen atoms of the lower alkenyl group is replaced byC₁₋₇-alkoxycarbonyl.

The term “lower alkoxycarbonylalkinyl” or“C₁₋₇-alkoxycarbonyl-C₃₋₇-alkinyl” refers to lower alkinyl groups asdefined above but having at least 3 carbon atoms wherein at least one ofthe hydrogen atoms of the lower alkinyl group is replaced byC₁₋₇-alkoxycarbonyl.

The term “lower alkoxycarbonylalkylaminocarbonyl” or“C₁₋₇-alkoxycarbonyl-C₁₋₇-alkylaminocarbonyl” refers to aminocarbonyl asdefined above wherein one of the hydrogen atoms of the amino group isreplaced by C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl. Preferred lowercarboxylalkylaminocarbonyl group is —CO—NH—CH₂—COOCH₃.

The term “C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl”refers to a C₁₋₇-alkylaminocarbonyl group (—CO—NR—, wherein R isC₁₋₇-alkyl) wherein one of the hydrogen atoms of the amino group isreplaced by C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl.

The term “lower alkoxycarbonylalkylaminocarbonylalkyl” or“C₁₋₇-alkoxycarbonyl-C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl” refers to alower alkyl group wherein one of the hydrogen atoms of the lower alkylgroup is replaced by “C₁₋₇-alkoxycarbonyl-C₁₋₇-alkylaminocarbonyl” asdefined above Preferred lower alkoxycarbonylalkylaminocarbonylalkylgroup is —CH₂—CO—NH—CH₂—COOCH₃.

The term“C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl”refers to a lower alkyl group wherein one of the hydrogen atoms of thelower alkyl group is replaced by“C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl”. Preferredgroup is —CH₂—CO—NCH₃—CH₂—COOCH₃.

The term “lower halogenalkyl” or “halogen-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a halogen atom, preferablyfluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,trifluoroethyl, 2,2-difluoroethyl, fluoromethyl and chloromethyl, withtrifluoromethyl or difluoromethyl being especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,preferably fluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkoxy groups are trifluoromethoxy, difluoromethoxy,fluormethoxy and chloromethoxy, with trifluoromethoxy being especiallypreferred.

The term hydroxy means the group —OH.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Among thepreferred lower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.

The term “lower hydroxyalkenyl” or “hydroxy-C₃₋₇-alkenyl” refers tolower alkenyl groups as defined above but having at least 3 carbon atomswherein at least one of the hydrogen atoms of the lower alkenyl group isreplaced by a hydroxy group. Among the preferred lower hydroxyalkenylgroups is hydroxyallyl.

The term “lower hydroxyalkinyl” or “hydroxy-C₃₋₇-alkinyl” refers tolower alkinyl groups as defined above but having at least 3 carbon atomswherein at least one of the hydrogen atoms of the lower alkinyl group isreplaced by a hydroxy group. Among the preferred lower hydroxyalkinylgroups is —C≡C—CH₂OH.

The term “lower hydroxyalkoxy” or “hydroxy-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a hydroxy group. Apreferred lower hydroxyalkoxy group is 2-hydroxyethoxy.

“Amino” refers to the group —NH₂. The term “C₁₋₇-alkylamino” means agroup —NHR, wherein R is lower alkyl and the term “lower alkyl” has thepreviously given significance.

The term “aminocarbonyl” refers to the group —CO—NH₂.

The term “carboxyl” means the group —COOH.

The term “lower carboxylalkyl” or “carboxyl-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a carboxyl group. Among thepreferred lower carboxyl alkyl groups are carboxylmethyl (—CH₂—COOH) andcarboxylethyl (—CH₂—CH₂—COOH), with carboxylmethyl being especiallypreferred.

The term “lower carboxylalkenyl” or “carboxyl-C₂₋₇-alkenyl” means loweralkenyl groups as defined herein before wherein one of the hydrogenatoms of the lower alkenyl group is replaced by carboxyl. Preferredlower carboxylalkenyl group is —CH═CH—CH₂—COOH.

The term “lower carboxylalkinyl” or “carboxyl-C₂₋₇-alkinyl” means alower alkinyl group as defined herein before wherein one of the hydrogenatoms of the lower alkinyl group is replaced by carboxyl. Preferredlower carboxylalkinyl group is —C≡C—CH₂—COOH.

The term “lower carboxylalkoxy” or “carboxyl-C₁₋₇-alkoxy” refers tolower alkoxy groups as defined above wherein at least one of thehydrogen atoms of the lower alkoxy group is replaced by a carboxylgroup. Among the preferred lower carboxylalkoxy groups is2-carboxyl-2-methylethoxy (—O—C(CH₃)₂—COOH).

The term “lower carboxylalkylaminocarbonyl” or“carboxyl-C₁₋₇-alkylaminocarbonyl” refers to aminocarbonyl as definedabove wherein one of the hydrogen atoms of the amino group is replacedby carboxyl-C₁₋₇-alkyl. Preferred lower carboxylalkylaminocarbonyl groupis —CO—NH—CH₂—COOH.

The term “lower carboxylalkyl(alkylamino)carbonyl” or“carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl” refers toC₁₋₇-alkylaminocarbonyl as defined above wherein the hydrogen atom ofthe alkylamino group is replaced by carboxyl-C₁₋₇-alkyl. Preferred lowercarboxylalkyl(alkylamino)carbonyl group is —CO—N(CH₃)—CH₂—COOH.

The term “lower carboxylalkylaminocarbonylalkyl” or“carboxyl-C₁₋₇-alkylamino-carbonyl-C₁₋₇-alkyl” refers to a lower alkylgroup wherein one of the hydrogen atoms of the lower alkyl group isreplaced by “carboxyl-C₁₋₇-alkylaminocarbonyl” as defined abovePreferred lower carboxylalkylaminocarbonylalkyl group is—CH₂—CO—NH—CH₂—COOH.

The term “carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl”refers to a lower alkyl group wherein one of the hydrogen atoms of thelower alkyl group is replaced by“carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl”, for example a group ofthe formula —CH₂—CO—NR—CH₂—COOH, wherein R is lower alkyl.

The term “lower hydroxyalkylaminocarbonyl” or“hydroxy-C₁₋₇-alkylaminocarbonyl” refers to aminocarbonyl as definedabove wherein one of the hydrogen atoms of the amino group is replacedby hydroxy-C₁₋₇-alkyl. Preferred lower hydroxyalkylaminocarbonyl groupsare —CO—NH—CH₂—CH₂—OH or —CO—NH—CH—(CH₂—OH)₂.

The term “di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl” refers to aminocarbonylas defined above wherein both of the hydrogen atoms of the amino groupare replaced by hydroxy-C₁₋₇-alkyl. Preferreddi-(hydroxy-C₁₋₇-alkyl)aminocarbonyl group is —CO—N(CH₂—CH₂—OH)₂.

The term “lower aminocarbonylalkylaminocarbonyl” or“aminocarbonyl-C₁₋₇-alkylaminocarbonyl” refers to aminocarbonyl asdefined above wherein one of the hydrogen atoms of the amino group isreplaced by aminocarbonyl-C₁₋₇-alkyl. A preferredaminocarbonyl-C₁₋₇-alkylaminocarbonyl group is —CO—NH—CH₂—CH₂—CO—NH₂.

The term “hydroxysulfonyl” means the group —SO₂—OH.

The term “lower hydroxysulfonylalkylaminocarbonyl” or“hydroxysulfonyl-C₁₋₇-alkylaminocarbonyl” refers to aminocarbonyl asdefined above wherein one of the hydrogen atoms of the amino group isreplaced by hydroxysulfonyl-C₁₋₇-alkyl. Preferredhydroxysulfonyl-C₁₋₇-alkylaminocarbonyl group is —CO—NH—CH₂—CH₂—SO₂—OH.

The term “lower hydroxysulfonylalkyl(alkylamino)carbonyl” or“hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl” refers toC₁₋₇-alkylaminocarbonyl wherein the hydrogen atom of the amino group isreplaced by hydroxysulfonyl-C₁₋₇-alkyl.

A preferred “di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl”group is —CO—NH—CH(—CH₂—CH₂—CO—OCH₃)₂.

The term “phenylcarbonyl” refers to the group —CO—R′ wherein R′ isphenyl.

The term “phenylaminocarbonyl” refers to the group —CO—NHR′ wherein R′is phenyl.

The term “lower phenylalkyl” or “phenyl-C₂₋₇-alkyl” means lower alkylgroups as defined above wherein one of the hydrogen atoms of the loweralkyl group is replaced by an optionally substituted phenyl group.

The term “lower phenylalkinyl” or “phenyl-C₂₋₇-alkenyl” refers to loweralkinyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkinyl group is replaced by optionally substitutedphenyl.

The term “heterocyclyl” in general refers to a saturated or partlyunsaturated 3-, 4-, 5-, 6- or 7-membered ring which can comprise one,two or three atoms selected from nitrogen, oxygen and/or sulphur.Examples of heterocyclyl rings include azirinyl, azetidinyl, oxetanyl,piperidinyl, piperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl,oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl, tetrahydrofuryl,dihydropyranyl, tetrahydropyranyl, and thiamorpholinyl. A preferredheterocyclyl group is oxetanyl.

The term “lower heterocyclylalkyl” or “heterocyclyl-C₁₋₇-alkyl” refersto lower alkyl groups as defined above wherein at least one of thehydrogen atoms of the lower alkyl group is replaced by a heterocyclylgroup as defined above.

“N-heterocyclyl” means a 3-, 4-, 5-, 6- or 7-membered saturatedheterocyclic ring containing a nitrogen atom (“N”) and optionallycontaining a further heteroatom selected from nitrogen, oxygen orsulfur. Preferably, the N-heterocyclyl ring is connected by the nitrogenatom to the carbon atom the ring is attached to. PreferredN-heterocyclyl rings are selected from the group consisting of azirinyl,azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl and azepanyl.

The term “heteroaryl” in general refers to an aromatic 5- or 6-memberedring which comprises one, two or three atoms selected from nitrogen,oxygen and/or sulphur, such as pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 2-oxo-1,2-dihydropyridinyl, oxazolyl, oxadiazolyl,isoxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, imidazolyl, furyl,thiazolyl and thienyl. The term “heteroaryl” further refers to bicyclicaromatic groups comprising two 5- or 6-membered rings, in which one orboth rings can contain one, two or three atoms selected from nitrogen,oxygen or sulphur, such as quinolinyl, isoquinolinyl, cinnolinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl,benzothiazolyl, benzotriazolyl, indolyl and indazolyl. Preferredheteroaryl group is furyl.

The term “lower heteroarylalkyl” or “heteroaryl-C₁₋₇-alkyl” refers tolower alkyl groups as defined above wherein at least one of the hydrogenatoms of the lower alkyl group is replaced by a heteroaryl group asdefined above.

The term “heteroarylcarbonyl” refers to the group —CO—R″ wherein R″ isheteroaryl as defined above.

The term “lower heteroarylcarbonylalkyl” or“heteroarylcarbonyl-C₁₋₇-alkyl” refers to lower alkyl groups as definedabove wherein at least one of the hydrogen atoms of the lower alkylgroup is replaced by a heteroarylcarbonyl group as defined above.

The term “heteroarylaminocarbonyl” refers to the group —CO—NH—R″ whereinR″ is heteroaryl as defined above.

The term “lower heteroarylalkylaminocarbonyl” or“heteroaryl-C₁₋₇-alkylaminocarbonyl” refers to a group —CO—NH—R^(x)wherein R^(x) is heteroaryl-C₁₋₇-alkyl as defined above.

The term “a five-membered heteroaryl” refers to an aromatic 5-memberedring which comprises at least one nitrogen atom and can in additioncomprise one to three atoms selected from nitrogen, oxygen and/orsulphur. Preferred five-membered heteroaryl rings are selected from thegroup consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, andthiazolyl. Preferably, the five-membered heteroaryl ring is connected bya nitrogen atom to the carbon atom the ring is attached to. Mostpreferably, the five-membered heteroaryl group is pyrrolyl.

Compounds of formula I can form pharmaceutically acceptable salts. Theterm “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are for example acid addition salts of compounds of formula I withphysiologically compatible mineral acids, such as hydrochloric acid,sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids,such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonicacid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylicacid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid,maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid,mandelic acid, succinic acid or salicylic acid. In addition,pharmaceutically acceptable salts may be prepared from addition of aninorganic base or an organic base to the free acid. Salts derived froman inorganic base include, but are not limited to, the sodium,potassium, lithium, ammonium, calcium, magnesium salts and the like.Salts derived from organic bases include, but are not limited to saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, lysine, arginine,N-ethylpiperidine, piperidine, polymine resins and the like. Thecompound of formula I can also be present in the form of zwitterions.Particularly preferred pharmaceutically acceptable salts of compounds offormula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g., hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The term“pharmaceutically acceptable salts” also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

In detail, the present invention relates to compounds of formula I,

wherein

-   A¹ is CR¹³ or N;-   A² is CR¹⁴ or N;-   R¹ and R² are independently from each other selected from the group    consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl,    cyano and C₁₋₇-alkoxy;-   R¹³ and R¹⁴ are independently from each other selected from the    group consisting of hydrogen, C₁₋₇-alkyl, halogen,    halogen-C₁₋₇-alkyl, cyano, C₁₋₇-alkoxy, amino and    C₁₋₇-alkylsulfanyl;-   R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy, cyano, C₃₋₇-cycloalkyl,    N-heterocyclyl, five-membered heteroaryl, phenyl and —NR¹⁵R¹⁶,    wherein R¹⁵ and R¹⁶ independently from each other are selected from    hydrogen, C₁₋₇-alkyl and C₃₋₇-cycloalkyl;-   R⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen-C₁₋₇-alkyl and C₃₋₇-cycloalkyl; or-   R³ and R⁴ or R³ and R¹⁴ together are —X—(CR¹⁷R¹⁸)_(n)— and form part    of a ring; wherein    -   X is selected from the group consisting of —CR¹⁹R²⁰—, O, S, C═O        and NR²¹;    -   R¹⁷ and R¹⁸ are independently from each other hydrogen or        C₁₋₇-alkyl;    -   R¹⁹ and R²⁰ are independently from each other selected from the        group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl,        and heterocyclyl optionally substituted by one or two groups        selected from C₁₋₇-alkyl and halogen,    -   or R¹⁹ and R²⁰ together with the C atom they are attached to        form a cyclopropyl or oxetanyl ring or together form a ═CH₂ or        ═CF₂ group;    -   R²¹ is selected from the group consisting of hydrogen,        C₁₋₇-alkyl, halogen-C₁₋₇-alkyl, C₃₋₇-cycloalkyl optionally        substituted by carboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl,        C₃₋₇-cycloalkyl-C₁₋₇-alkyl wherein the C₃₋₇-cycloalkyl is        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl, heterocyclyl, heterocyclyl-C₁₋₇-alkyl,        heteroaryl, heteroaryl-C₁₋₇-alkyl, carboxyl-C₁₋₇-alkyl,        C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,        C₁₋₇-alkylcarbonyloxy-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl, phenyl        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl, phenylcarbonyl wherein the phenyl is        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl, and phenylsulfonyl wherein the phenyl is        optionally substituted by carboxyl-C₁₋₇-alkyl or        C₁₋₇-alkoxycarbonyl,-   or R²¹ and a R¹⁷ together are —(CH₂)₃— and form part of a ring, or    -   R²¹ together with a pair of R¹⁷ and R¹⁸ are —CH═CH—CH═ and form        part of a ring;-   and n is 1, 2 or 3;-   B¹ is N or N⁺—O⁻;-   B² is CR⁷ or N;-   R⁵, R⁶ and R⁷ independently from each other are selected from the    group consisting of hydrogen, halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy,    halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, and cyano;-   and R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independently from each other    selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₂₋₇-alkenyl, C₂₋₇-alkinyl, halogen, halogen-C₁₋₇-alkyl,    C₁₋₇-alkoxy, halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkoxy,    hydroxy-C₁₋₇-alkyl, hydroxy-C₃₋₇-alkenyl, hydroxy-C₃₋₇-alkinyl,    cyano, carboxyl, C₁₋₇-alkoxycarbonyl, aminocarbonyl,    carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl, carboxyl-C₂₋₇-alkinyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl,    C₁₋₇-alkoxycarbonyl-C₂₋₇-alkinyl, carboxyl-C₁₋₇-alkoxy,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy, carboxyl-C₁₋₇-alkyl-aminocarbonyl,    carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,    carboxyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,    carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,    C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,    hydroxy-C₁₋₇-alkyl-aminocarbonyl,    di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,    aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,    hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,    hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,    di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl, phenyl    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl or C₁₋₇-alkoxycarbonyl, phenyl-carbonyl    wherein the phenyl is optionally substituted by one to three groups    selected from halogen, C₁₋₇-alkoxy, carboxyl and    C₁₋₇-alkoxycarbonyl, phenyl-aminocarbonyl wherein the phenyl is    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-C₁₋₇-alkyl    wherein the phenyl is optionally substituted by one to three groups    selected from halogen, C₁₋₇-alkoxy, carboxyl and    C₁₋₇-alkoxycarbonyl, phenyl-C₂₋₇-alkinyl wherein the phenyl is    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl optionally    substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-carbonyl    wherein the heteroaryl is optionally substituted by one to three    groups selected from halogen, C₁₋₇-alkoxy, carboxyl and    C₁₋₇-alkoxycarbonyl, heteroaryl-aminocarbonyl wherein the heteroaryl    is optionally substituted by one to three groups selected from    halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,    heteroaryl-C₁₋₇-alkyl wherein the heteroaryl is optionally    substituted by one to three groups selected from halogen,    C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,    heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein the heteroaryl is    optionally substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, and    heteroaryl-carbonyl-C₁₋₇-alkyl wherein the heteroaryl is optionally    substituted by one to three groups selected from halogen,    C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl;    and pharmaceutically acceptable salts thereof.

Compounds of formula I according to the present invention include those,wherein A¹ is CR¹³ and A² is CR¹⁴ or wherein A¹ is CR¹³ and A² is N,with R¹³ and R¹⁴ being independently from each other selected from thegroup consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl,cyano, C₁₋₇-alkoxy, amino and C₁₋₇-alkylsulfanyl.

Preferred are those compounds of formula I according to the presentinvention, wherein A¹ is CR¹³ and A² is CR¹⁴ and wherein R¹³ and R¹⁴ areindependently from each other selected from the group consisting ofhydrogen, halogen, halogen-C₁₋₇-alkyl and C₁₋₇-alkoxy. These arecompounds of the formula

Furthermore, compounds of formula I are preferred, wherein A¹ is CR¹³,A² is N, and R¹³ is selected from the group consisting of hydrogen,halogen, halogen-C₁₋₇-alkyl and C₁₋₇-alkoxy. These are compounds of theformula

In addition, compounds of formula I are preferred, wherein R¹ and R² areindependently from each other selected from the group consisting ofhydrogen, halogen and halogen-C₁₋₇-alkyl.

Compounds of formula I are further preferred, wherein R³ and R⁴ togetherare —X—(CR¹⁷R¹⁸)_(n)— and form part of a ring; wherein

X is —CR¹⁹R²⁰— or —NR²¹—;

R¹⁷ and R¹⁸ are independently from each other hydrogen or C₁₋₇-alkyl;R¹⁹ and R²⁰ are independently from each other selected from the groupconsisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl, andheterocyclyl optionally substituted by one or two groups selected fromC₁₋₇-alkyl and halogen,or R¹⁹ and R²⁰ together with the C atom they are attached to form acyclopropyl or oxetanyl ring or together form a ═CH₂ or ═CF₂ group;R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,halogen-C₁₋₇-alkyl, C₃₋₇-cycloalkyl optionally substituted bycarboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl, C₃₋₇-cycloalkyl-C₁₋₇-alkylwherein the C₃₋₇-cycloalkyl is optionally substituted bycarboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl, heterocyclyl,heterocyclyl-C₁₋₇-alkyl, heteroaryl, heteroaryl-C₁₋₇-alkyl,carboxyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkylcarbonyloxy-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl, phenyl optionallysubstituted by carboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl,phenylcarbonyl wherein the phenyl is optionally substituted bycarboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl, and phenylsulfonyl whereinthe phenyl is optionally substituted by carboxyl-C₁₋₇-alkyl orC₁₋₇-alkoxycarbonyl,or R²¹ and a R¹⁷ together are —(CH₂)₃— and form part of a ring, or R²¹together with a pair of R¹⁷ and R¹⁸ are —CH═CH—CH═— and form part of aring;and n is 1, 2 or 3.

Within this group, compounds are preferred, wherein X is —NR²¹—,

R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,C₃₋₇-cycloalkyl optionally substituted by carboxyl-C₁₋₇-alkyl orC₁₋₇-alkoxycarbonyl, C₃₋₇-cycloalkyl-C₁₋₇-alkyl, wherein theC₃₋₇-cycloalkyl is optionally substituted by carboxyl-C₁₋₇-alkyl orC₁₋₇-alkoxycarbonyl, and C₁₋₇-alkylsulfonyl,R¹⁷ and R¹⁸ are independently from each other hydrogen or methyl, and nis 2. These are compounds having the formula

In an embodiment within this group, R¹⁷ and R¹⁸ are both hydrogen.

Furthermore, compounds of formula I are especially preferred, wherein Xis —CH₂—, R¹⁷ and R¹⁸ are each independently hydrogen or methyl, and nis 2. These are compounds of the formula

In an embodiment within this group, R¹⁷ and R¹⁸ are both hydrogen.

In addition, compounds of formula I according to the invention arepreferred, wherein R³ and R¹⁴ together are —X—(CR¹⁷R¹⁸)_(n)— and formpart of a ring; wherein X is —NR²¹—, R²¹ is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl and C₃₋₇-cycloalkyl, R¹⁷ and R¹⁸ areindependently from each other hydrogen or methyl, and n is 2. These arethe compounds of the formula

In an embodiment within this group, R¹⁷ and R¹⁸ are both hydrogen, and nis 2.

R⁴ is preferably hydrogen or C₁₋₇-alkyl. More preferably, R⁴ is methyl.

Further preferred compounds of formula I of the present invention arethose, wherein R³ is selected from the group consisting of hydrogen,C₁₋₇-alkyl, C₁₋₇-alkoxy, N-heterocyclyl and —NR¹⁵R¹⁶, wherein R¹⁵ andR¹⁶ independently from each other are selected from hydrogen, C₁₋₇-alkyland C₃₋₇-cycloalkyl, and R⁴ is hydrogen or methyl, more preferablymethyl.

Furthermore, compounds of formula I are preferred, wherein B¹ is N orN⁺—O⁻ and B² is CR⁷, with R⁷ being selected from the group consisting ofhydrogen, halogen and C₁₋₇-alkyl. More preferably, B¹ is N. These arecompounds of the formula

Also preferred are compounds of formula I of the present invention,wherein B¹ is N and B² is N.

These are compounds of the formula

R⁵ and R⁶ are independently from each other selected from the groupconsisting of hydrogen, halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy,halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, and cyano. Preferred arecompounds of formula I, wherein R⁵ and R⁶ are independently from eachother selected from the group consisting of hydrogen, halogen andC₁₋₇-alkyl.

Compounds of the present invention are further preferred, wherein and atleast one or, in case R⁴ is hydrogen or C₁₋₇-alkyl, at least two of R⁸,R⁹, R¹⁰, R¹¹ and R¹² are selected from the group consisting of

C₁₋₇-alkyl, C₂₋₇-alkenyl, C₂₋₇-alkinyl, halogen, halogen-C₁₋₇-alkyl,C₁₋₇-alkoxy, halogen-C₁₋₇-alkoxy, hydroxy, hydroxy-C₁₋₇-alkoxy,hydroxy-C₁₋₇-alkyl, hydroxy-C₃₋₇-alkenyl, hydroxy-C₃₋₇-alkinyl, cyano,carboxyl, C₁₋₇-alkoxycarbonyl, aminocarbonyl, carboxyl-C₁₋₇-alkyl,carboxyl-C₂₋₇-alkenyl, carboxyl-C₂₋₇-alkinyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl,C₁₋₇-alkoxycarbonyl-C₂₋₇-alkinyl, carboxyl-C₁₋₇-alkoxy,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy, carboxyl-C₁₋₇-alkyl-aminocarbonyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,carboxyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,hydroxy-C₁₋₇-alkyl-aminocarbonyl, di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl, phenyloptionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-carbonyl whereinthe phenyl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,phenyl-aminocarbonyl wherein the phenyl is optionally substituted by oneto three groups selected from halogen, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, phenyl-C₁₋₇-alkyl wherein the phenyl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-C₂₋₇-alkinyl wherein the phenylis optionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-carbonyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,heteroaryl-aminocarbonyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, and heteroaryl-carbonyl-C₁₋₇-alkylwherein the heteroaryl is optionally substituted by one to three groupsselected from halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,and the other ones of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

More preferably, compounds of formula I are those, wherein at least twoof R⁸, R⁹, R¹⁰, R¹¹ and R¹² are selected from the group consisting ofhalogen, hydroxy, hydroxy-C₁₋₇-alkoxy, hydroxy-C₁₋₇-alkyl, cyano,carboxyl, C₁₋₇-alkoxycarbonyl, aminocarbonyl, carboxyl-C₁₋₇-alkoxy,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy, carboxyl-C₁₋₇-alkyl-aminocarbonyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxy-C₁₋₇-alkyl-aminocarbonyl, di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl,phenyl-aminocarbonyl wherein the phenyl is optionally substituted by oneto three groups selected from halogen, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, heteroaryl-aminocarbonyl wherein the heteroaryl isoptionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkylwherein the heteroaryl is optionally substituted by one to three groupsselected from halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, andheteroaryl-carbonyl-C₁₋₇-alkyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl,

and the other ones of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.

Especially preferred are compounds of formula I, wherein R⁸ and R¹¹ arehalogen and R⁹, R¹⁰ and R¹² are hydrogen.

Examples of preferred compounds are the following:

-   [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,-   [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(6,7-difluoro-3,4-dihydro-2H-quinolin-1-yl)-methanone,-   [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   2-{-[4-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-3,4-dihydro-2H-quinoxalin-1-ylmethyl}-cyclopropanecarboxylic    acid ethyl ester,-   (4-cyclopropylmethyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,-   [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,-   (6-chloro-4-cyclopropyl-7-fluoro-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,-   [4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,-   (6-chloro-4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,    and pharmaceutically-acceptable salts thereof.

Examples of preferred compounds also include the following:

-   4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-methyl-N-o-tolyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(2-methoxy-phenyl)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(2-methoxy-pyridin-3-yl)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-phenyl)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-methyl-N-(2-piperidin-1-yl-phenyl)-nicotinamide,-   N-(3,5-Bis-trifluoromethyl-phenyl)-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(4,5-difluoro-2-methoxy-phenyl)-N-methyl-nicotinamide,-   N-(5-chloro-2-dimethylamino-phenyl)-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(4,5-difluoro-2-methylamino-phenyl)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-N-methyl-nicotinamide,-   4-(2,5-dichloro-phenoxy)-N-methyl-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide,-   N-[4-chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide,    and pharmaceutically-acceptable salts thereof.

Examples of preferred compounds also include the following:

-   [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic    acid methyl ester,-   4-chloro-5-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phthalic    acid dimethyl ester,-   {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-acetic    acid methyl ester,-   {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-acetic    acid,-   ({2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-acetic    acid methyl ester,-   ({2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-acetic    acid,-   3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic    acid ethyl ester,    and pharmaceutically-acceptable salts thereof.

Examples of preferred compounds also include the following:

-   3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic    acid,-   2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-ethanesulfonic    acid,-   2-({2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-ethanesulfonic    acid,-   3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propane-1-sulfonic    acid,    and pharmaceutically-acceptable salts thereof.

Examples of preferred compounds also include the following:

-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-butyric    acid,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylic    acid methyl ester,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylic    acid,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoic    acid methyl ester,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoic    acid,-   2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylic    acid ethyl ester,-   2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylic    acid,-   5-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylic    acid ethyl ester,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-[1,3,4]thiadiazol-2-yl-benzamide,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(2-hydroxy-ethyl)-benzamide,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N,N-bis-(2-hydroxy-ethyl)-benzamide,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-benzamide,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzamide,-   N-(2-carbamoyl-ethyl)-2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzamide,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-heptanedioic    acid dimethyl ester,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxymethyl-phenoxy)-pyridin-3-yl]-methanone,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzonitrile,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone,-   {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-acetic    acid ethyl ester,-   {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-acetic    acid,-   2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionic    acid ethyl ester,-   2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionic    acid,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-{4-[2,5-dichloro-4-(2-hydroxy-ethoxy)-phenoxy]-pyridin-3-yl}-methanone,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-methanone,-   [4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic    acid methyl ester,-   2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic    acid,-   3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionic    acid ethyl ester,-   3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionic    acid,-   {2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-acetic    acid methyl ester,-   {2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-acetic    acid,-   2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide,-   2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide,-   [2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   [6-chloro-4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-methanone,-   [4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,-   [4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-methanone,-   [4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   [4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid    (2-methoxy-pyridin-3-yl)-methyl-amide and pharmaceutically    acceptable salts thereof.

Particularly advantageous compounds of formula I of the presentinvention are the following:

-   [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   (4-cyclopropylmethyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,-   (6-chloro-4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone,-   [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,-   {2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-acetic    acid,-   3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic    acid,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylic    acid,-   4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoic    acid,-   2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylic    acid,-   2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzonitrile,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-methanone,-   3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionic    acid,-   2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide,-   (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-methanone,-   [4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,    and pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salts of the compounds of formula I alsoindividually constitute advantageous compounds of the present invention.

Compounds of formula I can have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatized at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises

a) reacting a carboxylic acid of the formula II

wherein B¹, B² and R⁵ to R¹² are as defined above, with an amine of theformula III

wherein A¹, A² and R¹ to R⁴ are as defined above, in the presence of acoupling reagent under basic conditions to obtain a compound of theformula I

wherein A¹, A², B¹, B² and R¹ to R¹² are as defined above, and, ifdesired,converting the compound obtained into a pharmaceutically acceptablesalt.or, alternatively,b) coupling a compound of the formula IV

wherein A¹, A², B¹, B² and R¹ to R⁶ are as defined above and X means ahalogen atom or sulfonate, with a phenol of the formula V

wherein R⁸ to R¹² are as defined above, in the presence of a copper (I)source to obtain a compound of the formula I

wherein A¹, A², B¹, B² and R¹ to R¹² are as defined above, and, ifdesired,converting the compound obtained into a pharmaceutically acceptablesalt.

Appropriate coupling agents are for example N,N′-carbonyldiimidazole(CDI), N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride (EDCI),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),2-chloro-1-methylpyridinium iodide orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate(BOP). “Under basic conditions” means the presence of a base such asdiisopropylethylamine, triethylamine, N-methylmorpholine or4-(dimethylamino)-pyridine. The reaction is carried out in a suitablesolvent such as for example N,N-dimethylformamide (DMF),dimethylacetamide (DMAc), dichloromethane or dioxane, at temperaturesbetween 0° C. and ambient temperature.

A copper (I) source means a copper (I) salt such as copper (I) bromideor copper (I) iodide or copper (I) complexes such astetrakis(acetonitrile)copper(I) hexafluorophosphate. The coupling ispreferably carried out under heating or microwave assisted heating(typically to a temperature between 100 and 200° C., or up to theboiling temperature of the solvent) in an aprotic solvent such asN,N-dimethylformamide (DMF), dimethylacetamide (DMAc),N-methylpyrrolidone (NMP), ethylene glycol, acetonitrile and THF ormixtures thereof. Optionally a tertiary amine such as triethylamine,N-ethyl diisopropylamine (Hünigs base) or pyridine is also present.

The invention further relates to compounds of formula I as defined aboveobtainable according to a process as defined above.

In more detail, compounds of formula I according to the presentinvention can be prepared by the methods and procedures given below. Atypical procedure for the preparation of compounds of formula I isillustrated in Scheme 1.

Compounds of general formula IA and IB can be prepared for example asoutlined in Scheme 1 by reacting nicotinic acids of the generalstructure 1 in which X usually signifies a halogen such as iodine,bromine or chlorine with phenols 2 to provide bi-aryl ethers 3 (step a).In order to enhance the rate of conversion heating might be applied,whereby conventional heating or microwave assisted heating might beemployed using a suitable microwave irradiation apparatus. Furthermorethe reaction can be conducted in the presence of or without solvent(typically an aprotic polar solvent such as DMF (N,N-dimethylformamide),DMAc (dimethylacetamide), NMP (N-methylpyrrolidone), ethylene glycol,acetonitrile and THF or mixtures thereof; in some cases also a lesspolar solvent such as toluene might be appropriate) and in the presenceof or without a tertiary amine base such as triethylamine,N,N-diisopropylethylamine (Huenig's base) or pyridine and in thepresence of or without a copper(I) source such as copper(I) bromide orcopper(I) iodide. In some cases it might be advisable to conduct thereaction in the presence of copper (I) complexes with higher solubilitysuch as tetrakis(acetonitrile)copper(I) hexafluorophosphate (e.g., US06/028 7297 A1 (Johnson & Johnson)). Said reaction might be conductedwith or without copper metal (e.g., copper(0) nanopowder).Alternatively, the copper-mediated C(aryl)-O coupling reaction can beexecuted under basic conditions by using potassium- or cesium carbonate,potassium hydroxide, sodium methoxide, potassium tert-butylate or sodiumhydride (nucleophilic aromatic substitution type reaction), whereby X isa suitable leaving group such as chlorine, bromine, iodine, OSO₂alkyl,OSO₂fluoroalkyl, OSO₂aryl, mesylate (methanesulfonate) or triflate(trifluoromethanesulfonate). The starting materials of general structure1 (e.g., 4-chloro- or 4-bromo-nicotinic acids) are known compounds andare commercially available or can be prepared by numerous methods usingconventional reaction procedures generally known in the art. Forinstance, the carboxylic acid function in pyridine derivatives 1 mightbe prepared from the corresponding benzonitriles or from thecorresponding carboxylic esters by applying standard reaction conditionsused for such type of conversions known to a person skilled in the artsuch as, e.g. by acid catalyzed hydrolysis (e.g., sulfuric acid orhydrochloric acid) or by stirring with alkaline hydroxides (e.g.,lithium hydroxide, sodium hydroxide, potassium hydroxide) in a solventmixture consisting typically of tetrahydrofuran and water, optionally inthe presence of alcohols such as methanol or ethanol, wherebyconventional heating or heating by microwave irradiation might beapplied. These reactions can take place over a wide range oftemperatures ranging from ambient temperature to the reflux temperatureof the solvent employed. The phenols of formula 2 are also knowncompounds and are commercially available or can be prepared by numerousmethods using conventional reaction procedures generally known in theart.

Amide coupling of bi-aryl ether intermediates 3 with optionallysubstituted aryl- or heteroaryl-amines 4 (either commercially availableor accessible by methods described in references or by methods known inthe art) gives access to target structures of general structure IA (stepb). Amide couplings of this type are widely described in the literature(e.g., Comprehensive Organic Transformations: A Guide to FunctionalGroup Preparations, 2^(nd) Edition, Richard C. Larock, John Wiley &Sons, New York, N.Y. 1999) and can be accomplished by employing theusage of coupling reagents such as, e.g., N,N-carbonyldiimidazole (CDI),N,N-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N,N-tetramethyluronium tetrafluoroborate (TBTU)or 2-chloro-1-methylpyridinium iodide (Mukaiyama reagent; E. Bald, K.Saigo and T. Mukaiyama Chem. Lett. 1975, 4, 1163-1166) in a suitablesolvent like, e.g., N,N-dimethylformamide (DMF), dimethylacetamide(DMAc), dichloromethane or dioxane, optionally in the presence of a base(e.g., triethylamine, N,N-diisopropylethylamine (Huenig's base) or4-(dimethylamino)pyridine). Alternatively, target structures IA can beobtained by converting intermediates 3 into their acid chlorides bytreatment with, e.g., thionyl chloride, neat or optionally in a solventsuch as, e.g., dichloromethane and reaction of the acid chloride withamines 4 in an appropriate solvent such as, e.g., dichloromethane or DMF(N,N-dimethylformamide) and a base such as, e.g., triethylamine,N,N-diisopropylethylamine (Huenig's base), pyridinediisopropylethylamine, 4-(dimethylamino)pyridine or lithiumbis(trimethylsilyl)amide whereby theses reactions can take place over awide range of temperatures ranging from ambient temperature to thereflux temperature of the solvent employed.

In cases where aniline 4 is a primary amine (R⁴═H) leading to secondaryamides, alkylation (e.g., methylation, R⁴=Me) of the amide bond can beachieved by reaction with alkyl halides (e.g., methyl iodide or methylbromide) in the presence of a base such as, e.g. sodium hydride orpotassium tert-butoxide in an appropriate solvent like DMF(N,N-dimethylformamide), THF or mixtures thereof, at room temperature toelevated temperatures (step c).

Alternatively, compounds IA in which R⁴ signifies a lower alkyl groupcan be obtained by amide coupling of intermediates 3 with secondaryaryl- or heteroaryl-amines 4 (R⁴ as defined before) applying theconditions described before. Amines of this type are either commerciallyavailable or can be prepared by methods described in literature.

In those cases where the substituent R¹⁰ in compounds of formula IAsignifies or carries a carboxylic ester functionality (e.g. an alkylester such as, e.g. methyl, ethyl or tert-butyl), the esterfunctionality can be cleaved under basic (e.g. methyl or ethyl esterswith lithium or sodium hydroxide in polar solvents such as, e.g.methanol, water or tetrahydrofuran or mixtures of said solvents) orunder acidic conditions (e.g. a tert-butyl ester using concentratedhydrochloric acid in tetrahydrofuran or formic acid in an appropriatesolvent such as alcohols like, e.g. isopropanol) to furnish compounds IB(step d). Further esters include, but are not limited to, e.g. allyl orbenzyl esters that can be cleaved by methods known to those skilled inthe art and as described for example in “Protective Groups in OrganicChemistry” by T. W. Greene and P.G.M. Wutts, 2^(nd) Ed., 1991, WileyN.Y.) Optionally the substituent R¹⁰ in compounds of formula IA cansignify or carry a cyano group which can be either hydrolyzed to thecarboxylic acid under basic (e.g. with aqueous sodium or lithiumhydroxide) or under acidic conditions (e.g. hydrochloric or sulphuricacid), or can be converted to the corresponding tetrazole using standardprocedures such as, e.g. by treatment with sodium azide in the presenceof a Lewis acid (e.g. zinc(II) bromide) or ammonium chloride in water ororganic solvents like dichloromethane or N,N-dimethylformamide attemperatures between 0° C. and the boiling point of the solvent tofurnish compounds IB (step d). Compounds IB in which R¹⁰ carries atetrazole group can be also prepared by amide coupling of intermediates3 with amino- or amino-alkyl-substituted tetrazoles, that are eithercommercially available or can be prepared by literature methods. Thetetrazole group in amino- or amino-alkyl-substituted tetrazoles can beoptionally protected, for example with a triphenylmethyl (trityl)protective group that can be cleaved off after the reaction stepapplying methods known to those skilled in the art and as described inliterature.

Synthesis of structures of formula IA and IB can also be accomplished asoutlined in Scheme 2, employing an inverted reaction sequence, namely byfirst forming the amide bond between pyridyl carboxylic acids 1 andaryl- or heteroaryl-amines 4 (step a), followed by copper-mediatedC(pyridyl)-O coupling of the resulting intermediates 5 with phenols 2(step b). This provides then access to the target structures IA, whichin case of a secondary amide (if primary amines 4 were used) canoptionally be further alkylated applying the methods described before(step c). In cases where the amine moiety is the desired group ofvariation the strategy outlined in Scheme 1 is of particular interest.In contrary, the strategy depicted in Scheme 2 allows the phenol part ofthe structure to be varied in a rapid and parallel fashion. As describedunder Scheme 1, compounds of formula IA can be further converted intostructures IB applying the methods outlined before.

Compounds of the general structure IC and ID in which B² signifies CR⁷can be prepared according to Schemes 3 and 4. The synthesis of pyridineN-oxides via oxidation of the corresponding pyridines is widelydescribed in literature and can be accomplished by a variety of methods.For example, by using aqueous solutions of hydrogen peroxide in aceticacid or using dimethyl dioxirane or meta-chloroperbenzoic acid in anappropriate solvent such as, e.g. dichloromethane.

In those cases where compounds I contain other functional groups thatare reactive or can be oxidized under the applied reaction conditions itcan be advantageous to perform the oxidation of the nicotinic acidintermediates 1 as a the first synthetic step (Scheme 4, step a) withsubsequent amide coupling of the resulting N-oxide intermediates 6 witharyl- or heteroaryl-amines 4 (step b) and reacting the resultingintermediates 7 with phenols 2 under the conditions outlined before tofurnish compounds IC. Compounds of formula IC can be further convertedinto structures ID applying the methods described above.

If desired or required, functional groups present in I (such as—CO₂alkyl, amino groups, cyano groups and others) may be derivatized toother functional groups using typical standard procedures known to thoseskilled in the art (e.g. reduction of —CO₂alkyl to —CH₂OH with LiAlH₄,hydrolysis of —CO₂alkyl to CO₂H and subsequent optional conversion to anamide, acylation of amino groups and the like).

As described herein before, the compounds of formula I of the presentinvention can be used as medicaments for the treatment of diseases whichare associated with the modulation of GPBAR1 activity.

As compounds of formula I of the invention are agonists of the GPBAR1receptor, the compounds will be useful for lowering glucose, lipids, andinsulin resistance in diabetic patients and in non-diabetic patients whohave impaired glucose tolerance or who are in a pre-diabetic condition.The compounds of formula I are further useful to amelioratehyperinsulinemia, which often occurs in diabetic or pre-diabeticpatients, by modulating the swings in the level of serum glucose thatoften occurs in these patients. The compounds of formula I are alsouseful in reducing the risks associated with metabolic syndrome, inreducing the risk of developing atherosclerosis or delaying the onset ofatherosclerosis, and reducing the risk of angina, claudication, heartattack, stroke, and coronary artery disease. By keeping hyperglycemiaunder control, the compounds are useful to delay or for preventingvascular restenosis and diabetic retinopathy.

The compounds of formula I of the present invention are useful inimproving or restoring β-cell function, so that they may be useful intreating type 1 diabetes or in delaying or preventing a patient withtype 2 diabetes from needing insulin therapy. The compounds may beuseful for reducing appetite and body weight in obese subjects and maytherefore be useful in reducing the risk of co-morbidities associatedwith obesity such as hypertension, atherosclerosis, diabetes, anddyslipidemia. By elevating the levels of active GLP-1 in vivo, thecompounds are useful in treating neurological disorders such asAlzheimer's disease, multiple sclerosis, and schizophrenia.

Thus, the expression “diseases which are associated with the modulationof GPBAR1 activity” means diseases such as metabolic, cardiovascular,and inflammatory diseases, for example diabetes, particularly type 2diabetes or gestational diabetes, impaired fasting glucose, impairedglucose tolerance, insulin resistance, hyperglycemia, obesity, metabolicsyndrome, ischemia, myocardial infarction, retinopathy, vascularrestenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia orhyperlipidemia, lipid disorders such as low HDL cholesterol or high LDLcholesterol, high blood pressure, angina pectoris, coronary arterydisease, atherosclerosis, cardiac hypertrophy, rheumatoid arthritis,asthma, chronic obstructive pulmonary disease (COPD), psoriasis,ulcerative colitis, Crohn's disease, disorders associated withparenteral nutrition especially during small bowl syndrome, irritablebowl syndrome (IBS), allergy diseases, fatty liver, non-alcoholic fattyliver disease (NAFLD), liver fibrosis, non-alcoholic steatohepatitis(NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primarybiliary cirrhosis (PBC), kidney fibrosis, anorexia nervosa, bulimianervosa and neurological disorders such as Alzheimer's disease, multiplesclerosis, schizophrenia and impaired cognition.

In a preferable aspect, the expression ‘diseases which are associatedwith the modulation of GPBAR1 activity’ relates to diabetes,particularly type II diabetes, impaired fasting glucose, impairedglucose tolerance, hyperglycemia, metabolic syndrome, obesity,hypercholesterolemia and dyslipidemia.

The invention also relates to pharmaceutical compositions comprising acompound as defined above and a pharmaceutically acceptable carrierand/or adjuvant. More specifically, the invention relates topharmaceutical compositions useful for the treatment of diseases whichare associated with the modulation of GPBAR1 activity.

Further, the invention relates to compounds of formula I as definedabove for use as therapeutically active substances, particularly astherapeutically active substances for the treatment of diseases whichare associated with the modulation of GPBAR1 activity. Especiallypreferred are compounds of formula I for use in diabetes, preferablytype II diabetes, or hyperglycemia.

In another aspect, the invention relates to a method for the treatment aof diseases which are associated with the modulation of GPBAR1 activity,which method comprises administering a therapeutically active amount ofa compound of formula Ito a human being or animal. A method for thetreatment of diabetes, preferably type II diabetes, or hyperglycemia ispreferred.

The invention further relates to the use of compounds of formula I asdefined above for the treatment of diseases which are associated withthe modulation of GPBAR1 activity.

In addition, the invention relates to the use of compounds of formula Ias defined above for the preparation of medicaments for the treatment ofdiseases which are associated with the modulation of GPBAR1 activity.The use of compounds of formula I as defined above for the preparationof medicaments for the treatment of diabetes, preferably type IIdiabetes, or hyperglycemia is especially preferred.

Also contemplated herein is a combination therapy using one or morecompounds of formula I or compositions of the present invention, or apharmaceutically acceptable salts thereof, in combination with one ormore other pharmaceutically active compounds independently selected fromthe group consisting of the following:

(a) human peroxisome proliferator activated receptor (PPAR) gammaagonists (e.g., thiazolidinediones and glitazones, e.g., rosiglitazone,troglitazone, pioglitazone, englitazone, balaglitazone, andnetoglitazone),(b) biguanides such as metformin, metformin hydrochloride, buformin andphenformin,(c) dipeptidyl peptidase IV (DPP-4) inhibitors, such as sitagliptin,sitagliptin phosphate, saxagliptin, vildagliptin, alogliptin,carmegliptin, denagliptin sitagliptin, saxagliptin, and SYR-322,(d) incretins such as glucagon-like peptide-1 (GLP-1) receptor agonists(e.g., Exenatide (Byetta™), NN2211 (Liraglutide), GLP-1(7-36) amide andits analogs, GLP-1(7-37) and its analogs, AVE-0010 (ZP-10), R1583(taspoglutide), GSK-716155 (albiglutide, GSK/Human Genome Sciences),BRX-0585 (Pfizer/Biorexis) and CJC-1134-PC (Exendin-4:PC-DAC™) orglucose-dependent insulinotropic peptide (GIP),(e) insulin or insulin analogs such as LysPro insulin or inhaledformulations comprising insulin,(f) sulfonylureas such as tolazamide, chlorpropamide, glipizide,glimepiride, glyburide, glibenclamide, tolbutamide, acetohexamide orglypizide,(g) α-glucosidase inhibitors such as miglitol, acarbose, epalrestat, orvoglibose,(h) cholesterol biosynthesis inhibitors such as HMG CoA reductaseinhibitors, e.g., lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, cerivastatin, itavastin, nisvastatin and rivastatin, orsqualene epoxidase inhibitors, e.g., terbinafine,(i) plasma HDL-raising agents such as CETP inhibitors e.g., anacetrapib,torcetrapib and dalcetrapib, or PPAR alpha agonists, e.g., gemfibronzil,clofibrate, fenofibrate and bezafibrate,(j) PPAR dual alpha/gamma agonists such as muraglitazar, naveglitazar,aleglitazar, tesaglitazar, peliglitazar, farglitazar and JT-501,(k) bile acid sequestrants, e.g., anion exchange resins, or quaternaryamines (e.g., cholestyramine or colestipol)), or ileal bile acidtransporter inhibitors (BATi);(l) nicotinyl alcohol, nicotinic acid, niacinamide or salts thereof,(m) cholesterol absorption inhibitors such as ezetimibe or acyl-CoenzymeA:cholesterol O-acyl transferase (ACAT) inhibitors such as avasimibe,(n) selective estrogen receptor modulators such as raloxifene ortamoxifen) or LXR alpha or beta agonists, antagonists or partialagonists (e.g., 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol,T0901317 or GW3965);(o) microsomal triglyceride transfer protein (MTP) inhibitors,alpha2-antagonists and imidazolines (e.g., midaglizole, isaglidole,deriglidole, idazoxan, efaroxan, fluparoxan),(p) insulin secretagogues such as linogliride, nateglinide, repaglinide,mitiglinide calcium hydrate or meglitinide);(q) SGLT-2 inhibitors (e.g., dapagliflozin, sergliflozin and AVE 2268),(s) glucokinase activators such as the compounds disclosed in e.g., WO00/58293 A1;(t) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,(u) glucagon receptor antagonists,(v) anti-obesity agents such as fenfluramine, dexfenfluramine,phentiramine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists,neuropeptide Y2 agonists, MC4R (melanocortin 4 receptor) agonists,cannabinoid receptor 1 (CB-1) antagonists/inverse agonists, and B3adrenergic receptor agonists (e.g., GW-320659), nerve growth factoragonist (e.g., axokine), growth hormone agonists (e.g., AOD-9604), 5-HT(serotonin) reuptake/transporter inhibitors (e.g., Prozac), DA(dopamine) reuptake inhibitors (e.g., Buproprion), 5-HT, NA and DAreuptake blockers, steroidal plant extracts (e.g., P57), CCK-A(cholecystokinin-A) agonists, GHSR1a (growth hormone secretagoguereceptor) antagonist/inverse agonists, ghrelin antibody, MCH1R (melaninconcentrating hormone 1R) antagonists (e.g., SNAP 7941), MCH2R (melaninconcentrating hormone 2R) agonist/antagonists, H3 (histamine receptor 3)inverse agonists or antagonists, H1 (histamine 1 receptor) agonists, FAS(Fatty acid synthase) inhibitors, ACC-2 (acetyl-CoA carboxylase-1)inhibitors, DGAT-2 (diacylglycerol acyltransferase 2) inhibitors, DGAT-1(diacylglycerol acyltransferase 1) inhibitors, CRF (corticotropinreleasing factor) agonists, Galanin antagonists, UCP-1 (uncouplingprotein-1), 2 or 3 activators, leptin or a leptin derivatives, opioidantagonists, orexin antagonists, BRS3 agonists, GLP-1 (glucagons-likepeptide-1) agonists, IL-6 agonists, a-MSH agonists, AgRP antagonists,BRS3 (bombesin receptor subtype 3) agonists, 5-HT1B agonists, POMCantagonists, CNTF (ciliary neurotrophic factor or CNTF derivative),NN2211, Topiramate, glucocorticoid antagonist, Exendin-4 agonists,5-HT_(2C) (serotonin receptor 2C) agonists (e.g., Lorcaserin), PDE(phosphodiesterase) inhibitors, fatty acid transporter inhibitors,dicarboxylate transporter inhibitors, glucose transporter inhibitors,(w) anti-inflammatory agents such as cyclooxygenase-2 (COX-2) inhibitors(e.g., rofecoxib and celecoxib); glucocorticoids, azulfidine, thrombininhibitors (e.g., heparin, argatroban, melagatran, dabigatran), plateletaggregation inhibitors (e.g., glycoprotein IIb/IIIa fibrinogen receptorantagonists or aspirin), and ursodeoxycholic acid (UDCA) andnorursodeoxycholic acid (norUDCA), and(y) antihypertensives such as beta blockers (e.g., angiotensin IIreceptor antagonists such as losartan, eprosartan, irbesartan,tasosartan, telmisartan or valsartan; angiotensin converting enzymeinhibitors such as enalapril, captopril, cilazapril, ramapril,zofenopril, lisinopril and fosinopril; calcium channel blockers such asnifedipine and diltiazam and endothelian antagonists.

Such other pharmaceutically active compounds may be administered in anamount commonly used therefore, contemporaneously or sequentially with acompound of the formula I or a pharmaceutically acceptable salt thereof.In the treatment of patients who have type 2 diabetes, insulinresistance, obesity, metabolic syndrome, neurological disorders, andco-morbidities that accompany these diseases, more than onepharmaceutically active compound is commonly administered. The compoundsof formula I of this invention may generally be administered to apatient who is already taking one or more other drugs for theseconditions. When a compound of formula I is used contemporaneously withone or more other pharmaceutically active compounds, a pharmaceuticalcomposition in an unit dosage form containing such otherpharmaceutically active compounds and the compound of the formula I ispreferred. Thus, the invention also relates to a pharmaceuticalcomposition containing a compound of formula I in combination with oneor more other pharmaceutically active compounds as defined above. Whenused in combination with one or more other active ingredients, thecompound of formula I of the present invention and the otherpharmaceutically active compounds may be used in lower doses than wheneach is used singly. These kinds of pharmaceutical compositions are alsoincluded in the invention.

However, the combination therapy also includes therapies in which thecompound of formula I and one or more other pharmaceutically activecompounds are administered in different dosage forms, but withoverlapping schedules. The invention thus also relates to a method forthe treatment a of diseases which are associated with the modulation ofGPBAR1 activity, which method comprises administering a therapeuticallyactive amount of a compound of formula I in combination with one or moreother pharmaceutically active compounds to a human being or animal.

The following test was carried out in order to determine the activity ofthe compounds of formula I:

The cDNA of the human GPBAR1 receptor (Genbank: NM_(—)170699 with theexception of a silent C:G mutation at position 339 from the start codon)was amplified by polymerase chain reaction (PCR) from human cDNA andinserted into pCineo (Promega) by standard methods (Current Protocols inMolecular Biology, Wiley Press, ed. Ausubel et al.). The final clone wasverified by DNA sequence analysis. The plasmid was transfected into CHOcells deficient in dihydrofolate reductase activity (CHO-dhfr−) usingLipofectamine plus (Invitrogen). Clones were isolated in limiteddilution conditions and identified by activities in the cAMP assay usinglithocholic acid as agonist. A clonal cell line displaying the greatestactivity in cAMP increases was selected and identified as givingconsistently good responses for up to at least 20 passages.

cAMPAssay

CHO-dhfr(minus) cells expressing human GPBAR1 receptors are seeded 17-24hours prior to the experiment 50.000 cells per well in a black 96 wellplate with flat clear bottom (Corning Costar #3904) in DMEM (InvitrogenNo. 31331), 1×HT supplement, with 10% fetal calf serum and incubated at5% CO₂ and 37° C. in a humidified incubator. The growth medium wasexchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX andincubated at 30° C. for 30 min. Compounds were added to a final assayvolume of 100 μl and incubated for 30 min at 30° C. The assay wasstopped by the addition of 50 μA lysis reagent (Tris, NaCl, 1.5% TritonX100, 2.5% NP40, 10% NaN₃) and 50 μl detection solutions (20 μM mAbAlexa700-cAMP 1:1, and 48 μM Ruthenium-2-AHA-cAMP) and shaked for 2 h atroom temperature. The time-resolved energy transfer is measured by a TRFreader (Evotec Technologies GmbH, Hamburg Germany), equipped with aND:YAG laser as excitation source. The plate is measured twice with theexcitation at 355 nm and at the emission with a delay of 100 ns and agate of 100 ns, total exposure time 10 s at 730 (bandwith 30 nm) or 645nm (bandwith 75 nm), respectively. The measured signal at 730 nm has tobe corrected for the ruthenium background, the direct excitation ofAlexa and the buffer control. The FRET signal is calculated as follows:FRET=T730-Alexa730-P(T645-B645) with P═Ru730-B730/Ru645-B645, where T730is the test well measured at 730 nM, T645 is the test well measured at645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm,respectively. cAMP content is determined from the function of a standardcurve spanning from 10 μM to 0.13 nM cAMP.

EC₅₀ values were determined using Activity Base analysis (ID BusinessSolution, Limited). The EC₅₀ values for a wide range of bile acidsgenerated from this assay were in agreement with the values published inthe scientific literature. Specificity for GPBAR1 was tested innon-transfected CHO cells in the same assay as above.

The compounds according to formula I have an activity in the above assay(EC₅₀) preferably of 0.5 nM to 10 μM, more preferably of 0.5 nM to 1 μMand most preferably of 0.5 nM to 100 nM.

For example, the following compounds showed the following human EC₅₀values in the functional cAMP assay described above:

human EC₅₀ Example [μM] 1 0.04 2 0.1 3 0.1 4 0.003 5 1.8 6 0.003 7 0.3 80.002 9 0.05 10 0.7 11 0.01 12 0.1 13 0.2 14 0.1 15 0.1 16 0.04 17 1.918 1.4 19 0.1 20 0.4 21 0.4 22 0.9 23 0.2 24 0.1 25 1.7 26 0.004 270.004 28 0.004 29 0.1 30 0.4 31 0.1 32 0.9 33 0.02 34 0.3 35 0.1 36 0.337 0.9 38 0.04 39 0.4 40 0.2 41 0.1 42 0.1 43 0.1 44 0.02 45 0.6 46 0.0347 0.1 48 0.2 49 0.04 50 1.1 51 0.3 52 0.01 53 0.1 54 0.3 55 0.003 560.003 57 0.01 58 0.03 59 0.5 60 0.2 61 0.4 62 0.012 63 0.001 64 0.02 650.02 66 0.3 67 0.02 68 0.2 69 0.04 70 0.4 71 0.1 72 0.4 73 0.05 74 0.02275 0.01 76 0.04 77 0.4 78 0.3 79 0.01 80 0.09

The compounds of formula I and their pharmaceutically acceptable saltscan be used as medicaments, e.g., in the form of pharmaceuticalpreparations for enteral, parenteral or topical administration. They canbe administered, for example, perorally, e.g., in the form of tablets,coated tablets, dragées, hard and soft gelatin capsules, solutions,emulsions or suspensions, rectally, e.g., in the form of suppositories,parenterally, e.g., in the form of injection solutions or suspensions orinfusion solutions, or topically, e.g., in the form of ointments, creamsor oils. Oral administration is preferred.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable salts, optionally in combination with other therapeuticallyvaluable substances, into a galenical administration form together withsuitable, non-toxic, inert, therapeutically compatible solid or liquidcarrier materials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatincapsules. Suitable carrier materials for soft gelatin capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers might,however, be required in the case of soft gelatin capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 to 1000 mg,especially about 1 to 300 mg, comes into consideration. Depending onseverity of the disease and the precise pharmacokinetic profile thecompound could be administered with one or several daily dosage units,e.g., in 1 to 3 dosage units.

The pharmaceutical preparations conveniently contain about 1-500 mg,preferably 1-100 mg, of a compound of formula I.

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Abbreviations

CAS RN=chemical abstracts registration number, DMAc=dimethylacetamide,DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide, EI=electron impact, ESI=electrospray ionization, h=hour,HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate, HCl=hydrogen chloride, HPLC=high performance liquidchromatography, ISP=ion spray positive (mode), ISN=ion spray negative(mode), min=minutes, LiOH=lithium hydroxide, MgSO₄=magnesium sulfate,MPLC=medium performance liquid chromatography, MS=mass spectrum,NaHCO₃=sodium hydrogen carbonate, NaOH=sodium hydroxide, Na₂SO₄=sodiumsulfate, NH₄Cl=ammonium chloride, NMR=nuclear magnetic resonance,KOH=potassium hydroxide, P=protecting group, R=any group, rt=roomtemperature, SiO₂=silica gel, THF=tetrahydrofuran, X=halogen.

Example 1[4-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone

To a solution of 0.16 g (0.56 mmol) 4-(2,5-dichloro-phenoxy)-nicotinicacid in 3 mL N,N-dimethylformamide were added 0.225 g (0.59 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 0.29 mL (1.69 mmol) N,N-diisopropylethylamine. To the light yellowsolution 0.07 mL (0.59 mmol) 1,2,3,4-tetrahydroquinoline (commerciallyavailable; CAS RN 635-46-1) was added and the resulting light yellowsolution was stirred at room temperature for 23 hours. The reactionmixture was poured on water and extracted three times with ethylacetate. The combined organic layers were washed with water and brine,dried over magnesium sulfate, filtered, treated with silica gel andevaporated. The resulting powder was purified by silica gelchromatography using a MPLC system (20 g silica gel column, CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate(100:0 to 50:50). The product-containing fractions were combined andevaporated to give 165 mg (73%) of the desired compound as a light brownsolid. MS (ESI): m/z=399.06 [M+H]⁺.

Intermediate 4-(2,5-Dichloro-phenoxy)-nicotinic acid

To a suspension of 10 g (63.47 mmol) 4-chloronicotinic acid(commercially available; CAS RN 10177-29-4) and 11.38 g (69.81 mmol)2,5-dichlorophenol (commercially available CAS RN 583-78-8) in 50 mL dryN,N-dimethylformamide were added 17.55 g (126.94 mmol) potassiumcarbonate, 1.21 g (6.35 mmol) copper(I)iodide and 1.21 g (19.04 mmol)copper nanopowder. The green suspension was stirred at 120° C. (oil bathtemperature) for 3 hours and then cooled down to 80° C. At thattemperature, 400 mL water were added, the suspension was stirred at 80°C. for 5 min., filtered over Dicalite® speed plus (Acros) and the filtercake washed twice with 50 mL water. The resulting filtrate was extractedthree times with ethyl acetate and then the pH was adjusted to 4-5 using140 mL 1M aqueous hydrochloric acid. The resulting green, turbidsolution was treated with ethyl acetate, stirred for 5 min. andfiltered. The blue solid that had formed was filtered off and the layersof the filtrate were separated. The aqueous layer was saturated withsolid sodium chloride and extracted three times with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered and evaporated. To the resulting solid 200 mLsaturated aqueous potassium carbonate solution and 200 mL ethyl acetatewere added. The aqueous layer was extracted twice with 200 mL ethylacetate and the pH was adjusted to 4 using 25% aqueous hydrochloricacid. The resulting suspension was extracted three times with ethylacetate. The combined organic layers were washed three times with waterand once with brine, dried over magnesium sulfate, filtered andevaporated to give the desired compound as a light brown solid (7.29 g,40%). MS (ESI): m/z=281.8 [M−H]⁻.

Example 2[4-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(6,7-difluoro-3,4-dihydro-2H-quinolin-1-yl)-methanone

The title compound was prepared in analogy to Example 1, from6,7-difluoro-1,2,3,4-tetrahydro-quinoline (commercially available; CASRN 953717-64-1) and 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1,intermediate). Light brown gum (28%). MS (ESI): m/z=435.04 [M+H]⁺.

Example 3[4-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone

The title compound was prepared in analogy to Example 1, from1,2,3,4-tetrahydro-quinoxaline (commercially available; CAS RN3476-89-9) and 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1,intermediate). Light yellow foam (99%). MS (ESI): m/z=400.06 [M+H]⁺.

Example 4[4-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

A solution of 0.12 g (0.30 mmol)[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 3) in 1 mL N,N-dimethylformamide was treated with 0.014 g (0.32mmol) sodium hydride (60% suspension in mineral oil) upon which gasevolution set in and a colour change occurred. After stirring for 30min., 0.022 mL (0.36 mmol) iodomethane were added. After stirring for 7hours at room temperature, the reaction mixture was poured onto waterand was extracted three times with ethyl acetate. The combined organiclayers were washed with water and brine, dried over magnesium sulfate,filtered, treated with silica gel and evaporated to dryness. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (20 g silica gel column, CombiFlash Companion, Isco Inc.) elutingwith a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give thedesired compound as an orange solid (32 mg, 26%). MS (ESI): m/z=414.077[M+H]⁺.

Example 52-{4-[4-(2,5-Dichloro-phenoxy)-pyridine-3-carbonyl]-3,4-dihydro-2H-quinoxalin-1-ylmethyl}-cyclopropanecarboxylicacid ethyl ester

To a solution of 0.10 g (0.25 mmol)[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 3) were added 0.036 g (0.25 mmol) ethyl2-formyl-1-cyclopropane-carboxylate (commercially available, CAS RN20417-61-2), 0.008 g (0.026 mmol) dibutyltin dichloride and 0.06 mL(0.50 mmol) phenylsilane. The resulting solution was heated for 10 min.in a microwave oven at 150° C. The light yellow solution was evaporatedand dissolved in acetonitrile containing a few drops ofN,N-dimethylformamide. The suspension was filtered using a syringe microfilter and purified on a preparative HPLC system (Phenomenex Geminicolumn) using a gradient of acetonitrile:water (containing 0.05% formicacid) (10:90 to 98:2) to give 60 mg (46%) of the desired compound as alight brown foam. MS (ESI): m/z=526.13 [M+H]⁺.

Example 6(4-Cyclopropylmethyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

The title compound was prepared in analogy to Example 5, from[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 3), cyclopropanecarboxaldehyde (commercially available; CAS RN1489-69-6), dibutyltin dichloride and phenylsilane. Light brown solid(53%). MS (ESI): m/z=454.109 [M+H]⁺.

Example 7[4-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(4-methanesulfonyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

To a solution of 0.10 g (0.25 mmol)[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 3) in 2 mL dichloromethane were added 0.08 mL (0.50 mmol)N,N-diisopropylethylamine followed by dropwise addition of 0.02 mL (0.27mmol) methanesulfonylchloride. After 16 hours another 0.08 mL (0.50mmol) N,N-diisopropylethylamine and 0.02 mL (0.27 mmol)methanesulfonylchloride were added. The reaction mixture was poured onwater and was extracted three times with dichloromethane. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered, treated with silica gel and evaporated. The resulting powderwas purified by silica gel chromatography using a MPLC system (10 gsilical gel column, CombiFlash Companion, Isco Inc.) eluting with agradient of n-heptane:ethyl acetate (100:0 to 50:50) followed by asecond chromatography on a 10 g silica gel column using a gradient fromn-heptane:tert-butyl methyl ether (100:0 to 25:75) to give 31 mg (26%)of the desired compound as a light brown foam. MS (ESI): m/z=478.039[M+H]⁺.

Example 8(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline. Light yellow foam (72%).MS (ESI): m/z=440.092 [M+H]⁺.

Intermediates a) 1-Cyclopropyl-1,2,3,4-tetrahydro-quinoxaline

To a stirred suspension of1-cyclopropyl-1,4-dihydro-quinoxaline-2,3-dione (10.0 g, 49.45 mmol, 1.0equiv) in tetrahydrofuran (500 mL) was added dropwise a 1 M solution ofborane-tetrahydrofuran complex (108.8 mL, 108.8 mmol, 2.2 equiv; [CAS RN14044-65-6]) and the reaction mixture stirred at room temperature overnight. The solvent was removed by evaporation under reduced pressure andthe crude reaction mixture extracted from a saturated aqueous solutionof sodium bicarbonate (100 mL) with ethyl acetate (three times 100 mL).The combined organic phases were dried over sodium sulfate and purifiedby silica gel column chromatography using a MPLC system (CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetateto give 4.2 g (49%) of the title compound as a light yellow solid. MS(ISP): m/z=175.4 [M+H]⁺.

b) 1-Cyclopropyl-1,4-dihydro-quinoxaline-2,3-dione

To a solution of1-cyclopropyl-4-hydroxy-1,4-dihydro-quinoxaline-2,3-dione (31.0 g, 0.14mol, 1.0 equiv) in N,N-dimethylformamide (250 mL) was addedtriphenylphosphine (55.9 g, 0.21 mol, 1.5 equiv; [CAS RN 603-35-0]) andthe reaction mixture stirred at 135° C. for 4 hours. The reactionmixture was cooled down to 0° C. and dichloromethane (400 mL) was added.The suspension was stirred for 30 min., filtered and washed withdichloromethane (200 mL) providing 23.8 g (83%) of the title compound asa white solid. MS (ISN): m/z=203.1 [M+H]⁺.

c) 1-Cyclopropyl-4-hydroxy-1,4-dihydro-quinoxaline-2,3-dione

To a solution of N-cyclopropyl-N-(2-nitro-phenyl)-oxalamic acid methylester (45.0 g, 0.17 mol, 1.0 equiv) in methanol (400 mL) was addedpalladium on carbon (4.52 g, 0.0043 mol, 0.025 equiv; 10% Pd/C; [CAS RN7440-05-3]) and the reaction mixture stirred under an atmosphere ofhydrogen (1.2 bar) at room temperature for 2 hours. The reaction mixturewas diluted with ethyl acetate (400 mL), filtered over Celite® and thesolvent mixture removed by evaporation under reduced pressure to give31.2 g (84%) of the title compound as a light yellow solid. MS (ISN):m/z=219.1 [M+H]⁺.

d) N-Cyclopropyl-N-(2-nitro-phenyl)-oxalamic acid methyl ester

To a solution of cyclopropyl-(2-nitro-phenyl)-amine (32.0 g, 0.18 mol,1.0 equiv) in dichloromethane (320 mL) was added triethylamine (18.2 g,25.0 mL, 0.18 mol, 1.0 equiv; [CAS RN 121-44-8]) and methyl oxalylchloride (22.0 g, 16.5 mL, 0.18 mol, 1.0 equiv; [CAS RN 5781-53-3])slowly at 0° C. After the addition was completed the reaction mixturewas stirred at room temperature for 72 h. The reaction mixture wasextracted from a saturated aqueous sodium bicarbonate solution (300 mL)with dichloromethane (three times 200 mL) and the combined organicphases dried over magnesium sulfate. Purification by silica gel columnchromatography using a MPLC system (CombiFlash Companion, Isco Inc.)eluting with a mixture of n-heptane:ethyl acetate (2:1) afforded 45.2 g(95%) of the title compound as a white solid. MS (ISP): m/z=265.1[M+H]⁺.

e) Cyclopropyl-(2-nitro-phenyl)-amine

To cyclopropylamine (27.3 g, 33.1 mL, 0.48 mol, 2.25 equiv; [CAS RN765-30-0]) was added dropwise 2-fluoronitrobenzene (30.0 g, 0.21 mol,1.0 equiv; [CAS RN 1493-27-2]) over 1 hours at 30° C. and stirring ofthe reaction mixture continued at room temperature for 18 h. Thereaction mixture was extracted from a saturated aqueous solution ofsodium bicarbonate (500 mL) with ethyl acetate (three times 300 mL) andthe combined organic phases were dried over magnesium sulfate.Purification by silica gel column chromatography using a MPLC system(CombiFlash Companion, Isco Inc.) eluting with a mixture ofn-heptane:ethyl acetate (9:1) afforded 32.4 g (86%) of the titlecompound as a yellow oil. MS (ISP): m/z=178.0 [M+H]⁺.

Example 9(6-Chloro-4-cyclopropyl-7-fluoro-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and7-chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-quinoxaline and usinga gradient of n-heptane:ethyl acetate (100:0 to 0:100) for thechromatographic purification. Light yellow solid (19%). MS (ESI):m/z=494.041 [M+H]⁺.

Intermediates a)7-Chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-quinoxaline

To a suspension of 390 mg (1.532 mmol)7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-quinoxaline-2,3-dione in 20mL tetrahydrofuran was added 3.37 mL (3.369 mmol) 1M boranetetrahydrofuran complex. The reaction mixture was stirred for 6 hours atroom temperature. The reaction mixture was poured on 30 mL 10% aqueoussodium bicarbonate solution and 30 mL ethyl acetate. The mixture wasstirred for 30 min. at room temperature and the layers were separated.The aqueous layer was extracted a second time with 30 mL ethyl acetate.The organic layers were washed with 30 mL brine, dried over magnesiumsulfate, filtered and concentrated under vacuum. The compound waspurified by silica gel chromatography using a MPLC system (CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate(100:0 to 40:60) to give 211 mg (61%) of the desired compound as a whitesolid. MS (ESI): m/z=225.0 [M+H]⁺.

b) 7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-quinoxaline-2,3-dione

To a solution of 685 mg (2.531 mmol)6-chloro-4-cyclopropyl-7-fluoro-1-hydroxy-1,4-dihydro-quinoxaline-2,3-dionein 10 mL N,N-dimethylformamide was added 996 mg (3.796 mmol)triphenylphosphine. The reaction mixture was stirred for 4 hours at 135°C. The reaction mixture was concentrated under vacuum (15 mbar/55° C.).The residue was suspended in 20 mL dichloromethane. The suspension wasstirred for 30 min at 0° C. and filtered and washed with 20 mLdichloromethane. White solid (63%). MS (ESI): m/z=255.034 [M+H]⁺.

c)6-Chloro-4-cyclopropyl-7-fluoro-1-hydroxy-1,4-dihydro-quinoxaline-2,3-dione

To a solution of 1.2 g (3.789 mmol)N-(5-chloro-4-fluoro-2-nitro-phenyl)-N-cyclopropyl-oxalamic acid methylester in 15 mL MeOH was added 120 mg Pd(C) 10% on charcoal. The reactionmixture was stirred for 2 hours under hydrogen atmosphere at 1.2 bar atroom temperature. 30 mL ethyl acetate was added and the reaction mixturewas filtered over Dicalite® speed plus (Acros) speed plus (Acros) andconcentrated under vacuum. Light yellow solid (68%). MS (ESI):m/z=269.014 [M+H]⁺.

d) N-(5-Chloro-4-fluoro-2-nitro-phenyl)-N-cyclopropyl-oxalamic acidmethyl ester

To a solution of 1.0 g (4.336 mmol)(5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-amine (J. Med. Chem.1992, 35(8), 1385) in 15 mL dichloromethane was added 439 mg (4.336mmol) triethylamine and 531 mg (4.336 mmol) mono-methyl oxalyl chlorideat 0° C. The reaction mixture was stirred for 72 hours at roomtemperature. The reaction mixture was poured on 30 mL sodium bicarbonate10% in water and 30 mL dichloromethane. The layers were separated. Theaqueous layer was extracted a second time with 30 mL dichloromethane.The organic layers were washed with 30 mL brine, dried over magnesiumsulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography using a MPLC system (CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate(100:0 to 40:60) to give the compound as a light yellow solid (90%). MS(ESI): m/z=316.0 [M+H]⁺.

Example 10[4-(2,5-Dichloro-phenoxy)-1-oxy-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone

To an ice-cold solution of 0.27 g (0.68 mmol)[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone(Example 1) in 3 mL dichloromethane was added 0.189 g (0.84 mmol)m-chloroperbenzoic acid (Aldrich, CAS RN 937-14-4). The light yellowsolution was stirred at room temperature for 2.75 hours and then pouredon a saturated aqueous sodium bicarbonate solution and extracted threetimes with dichloromethane. The combined organic layers were washed withbrine, dried over magnesium sulfate, filtered, treated with silica geland evaporated. The resulting powder was purified by silica gelchromatography using a MPLC system (CombiFlash Companion, Isco Inc.)eluting with a gradient of n-heptane:ethyl acetate:methanol (100:0:0 to0:100:0 to 0:0:100) to give 279 mg (99%) of the desired compound as alight brown foam. MS (ESI): m/z=415.061 [M+H]⁺.

Example 11(6-Chloro-4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone

To an ice-cold suspension of 0.61 g (1.39 mmol)(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-methanone(Example 8) in 3 mL dichloromethane were added 0.388 g (1.73 mmol)m-chloroperbenzoic acid (Aldrich, CAS RN 937-14-4). The cooling bath wasremoved, the reaction stirred at room temperature for 45 min., poured ona saturated solution of aqueous sodium bicarbonate and extracted threetimes with dichloromethane. The organic layers were washed with asaturated solution of aqueous sodium bicarbonate and brine, dried overmagnesium sulfate, filtered, treated with silica gel and evaporated. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (20 g silica gel column, CombiFlash Companion, Isco Inc.) with agradient of n-heptane:ethyl acetate:methanol (100:0:0 to 0:100:0 to0:0:100). From the resulting light brown foam (0.51 g; MS (ESI):m/z=456.087 [M+H]⁺), 0.20 g (0.44 mmol) were dissolved in 8 mLtetrahydrofuran and 0.09 mL (0.44 mmol) hexamethyldisilazane and 0.08 mL(1.1 mmol) methyl chloroformate were added. The resulting brown, turbidsolution was stirred for 1.5 hours at room temperature, poured onsaturated aqueous sodium bicarbonate solution and was extracted threetimes with ethyl acetate. The organic layers were washed with brine,dried over magnesium sulfate, filtered, treated with silica gel andevaporated. The resulting powder was purified by silica gelchromatography using a MPLC system (10 g silica gel column, CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate(100:0 to 25:75). The resulting orange solid (0.13 g) was dissolved inacetonitrile and a few drops N,N-dimethylformamide, filtered using asyringe micro filter and purified two times on a preparative HPLC system(Phenomenex Gemini column) using a gradient of acetonitrile:water(containing 0.05% formic acid) (10:90 to 98:2) to give 65 mg (31%) ofthe title compound as a light brown foam. MS (ESI): m/z=474.054 [M+H]⁺.

Example 124-(2,5-Dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-N-methyl-nicotinamide

To an ice-cold suspension of 0.07 g (0.17 mmol)4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-nicotinamide in 1mL tetrahydrofuran were added 0.019 g (0.17 mmol) potassiumtert-butoxide followed by 10 μl (0.18 mmol) iodomethane. The suspensionwas stirred at room temperature for 16 hours, poured onto 10% aqueouscitric acid solution and was extracted three times with ethyl acetate.The combined organic layers were washed with brine, dried over magnesiumsulfate, filtered, treated with silica gel and evaporated to dryness.The resulting powder was purified by silica gel chromatography using aMPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient ofn-heptane:ethyl acetate (100:0 to 50:50) to give 32 mg (44%) of thetitle compound as a white solid. MS (ESI): m/z=421.052 [M+H]⁺.

Intermediate4-(2,5-Dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and5-fluoro-2-methoxy-phenylamine (commercially available; CAS RN1978-39-8). White solid (74%). MS (ESI): m/z=407.036 [M+H]⁺.

Example 13 4-(2,5-Dichloro-phenoxy)-N-methyl-N-o-tolyl-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) andN-methyl-o-toluidine (commercially available; CAS RN 611-21-2) and usinga gradient of n-heptane:ethyl acetate (100:0 to 40:60). The compound wasfurther purified through a second preparative HPLC chromatography(Phenomenex Gemini column) using a gradient of acetonitrile:water(containing 0.05% formic acid) (10:90 to 98:2). White solid (35%). MS(ESI): m/z=387.066 [M+H]⁺.

Example 144-(2,5-Dichloro-phenoxy)-N-(2-methoxy-phenyl)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and2-methoxy-N-methylaniline (commercially available; CAS RN 10541-78-3)and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60). Thecompound was further purified through a second preparative HPLCchromatography (Phenomenex Gemini column) using a gradient ofacetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5). Whitesolid (57%). MS (ESI): m/z=403.062 [M+H]⁺.

Example 154-(2,5-Dichloro-phenoxy)-N-(2-methoxy-pyridin-3-yl)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, from4-(2,5-dichloro-phenoxy)-N-(2-methoxy-pyridin-3-yl)-nicotinamide. Thecompound was purified by preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile:water (50:50 to 95:5). Light yellowsolid (37%). MS (ESI): m/z=404.057 [M+H]⁺.

Intermediate4-(2,5-Dichloro-phenoxy)-N-(2-methoxy-pyridin-3-yl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and3-amino-2-methoxypyridine (commercially available, CAS RN 20265-38-7).The compound was purified by preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile:water (10:90 to 95:5). Light brownsolid (28%). MS (ESI): m/z=390.040 [M+H]⁺.

Example 164-(2,5-Dichloro-phenoxy)-N-(2-dimethylamino-phenyl)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, from4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-phenyl)-nicotinamide. Thecompound was purified by silica gel chromatography using a MPLC system(CombiFlash Companion, Isco Inc.) eluting with a gradient ofn-heptane:ethyl acetate (100:0 to 50:50), followed by a secondchromatography on a preparative HPLC system (Phenomenex Gemini column)eluting with a gradient of acetonitrile:water (containing 0.05% formicacid) (10:90 to 98:2). Colorless oil (47%). MS (ESI): m/z=416.092[M+H]⁺.

Intermediate4-(2,5-Dichloro-phenoxy)-N-(2-dimethylamino-phenyl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) andN,N-dimethylbenzene-1,2-diamine (commercially available, CAS RN2836-03-5). The compound was purified by preparative HPLC (PhenomenexGemini column) using a gradient of acetonitrile:water (containing 0.05%formic acid) (10:90 to 98:2). Light brown foam (71%). MS (ESI):m/z=402.078 [M+H]⁺.

Example 174-(2,5-Dichloro-phenoxy)-N-methyl-N-(2-piperidin-1-yl-phenyl)-nicotinamide

The title compound was prepared in analogy to Example 12, from4-(2,5-dichloro-phenoxy)-N-(2-piperidin-1-yl-phenyl)-nicotinamide. Thecompound was purified by preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2). White foam (88%). MS (ESI): 456.125 [M+H]⁺.

Intermediate4-(2,5-Dichloro-phenoxy)-N-(2-piperidin-1-yl-phenyl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and2-piperidin-1-yl-phenylamine (commercially available; CAS RN39643-31-7). White foam (90%). MS (ESI): 442.108 [M+H]⁺.

Example 18N-(3,5-Bis-trifluoromethyl-phenyl)-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, fromN-(3,5-bis-trifluoromethyl-phenyl)-4-(2,5-dichloro-phenoxy)-nicotinamide.The compound was purified by preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2). White foam (35%). MS (ESI): m/z=509.025 [M+H]⁺.

IntermediateN-(3,5-Bis-trifluoromethyl-phenyl)-4-(2,5-dichloro-phenoxy)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and3,5-bis(trifluoromethyl)aniline (commercially available; CAS RN328-74-5) and using a gradient of n-heptane:ethyl acetate (100:0 to40:60) for the chromatographic purification. Light yellow foam (44%). MS(ESI): m/z=495.010 [M+H]⁺.

Example 194-(2,5-Dichloro-phenoxy)-N-(4,5-difluoro-2-methoxy-phenyl)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, from4-(2,5-dichloro-phenoxy)-N-(4,5-difluoro-2-methoxy-phenyl)-nicotinamide.The residue was purified by preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2). White solid (51%). MS (ESI): m/z=439.042 [M+H]⁺.

Intermediate4-(2,5-Dichloro-phenoxy)-N-(4,5-difluoro-2-methoxy-phenyl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and4,5-difluoro-2-methoxyaniline (commercially available; CAS RN1017779-71-3) and using a gradient of n-heptane:ethyl acetate (100:0 to40:60) for the chromatographic purification. White solid (80%). MS(ESI): m/z=425.027 [M+H]⁺.

Example 20N-(5-Chloro-2-dimethylamino-phenyl)-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, fromN-(5-chloro-2-dimethylamino-phenyl)-4-(2,5-dichloro-phenoxy)-nicotinamide.White foam (85%). MS (ESI): m/z=450.054 [M+H]⁺.

IntermediateN-(5-Chloro-2-dimethylamino-phenyl)-4-(2,5-dichloro-phenoxy)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate),(2-amino-4-chlorphenyl)dimethylamine dihydrochloride (commerciallyavailable, CAS RN 183251-88-9), using 5 mole equivalents of base andusing a gradient of n-heptane:ethyl acetate (100:0 to 50:50) for thechromatographic purification. White solid (72%). MS (ESI): m/z=436.038[M+H]⁺.

Example 214-(2,5-Dichloro-phenoxy)-N-(4,5-difluoro-2-methylamino-phenyl)-N-methyl-nicotinamide

A solution of 100 mg (0.186 mmol)(2-{[4-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-methyl-amino}-4,5-difluoro-phenyl)-methyl-carbamicacid tert-butyl ester in 1.5 mL 1M aqueous hydrochloric acid was stirredfor 4 hours at 90° C. The reaction mixture was cooled down to roomtemperature and 2 mL 1M aqueous sodium hydroxide solution and 1 mLacetonitrile were added. The light yellow solution was directly purifiedby preparative HPLC (Phenomenex Gemini column) with a gradient ofacetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) togive 18 mg (22%) of the title compound as a colorless solid. MS (ESI):m/z=438.058 [M+H]⁺.

Intermediates a)(2-{[4-(2,5-Dichloro-phenoxy)-pyridine-3-carbonyl]-methyl-amino}-4,5-difluoro-phenyl)-methyl-carbamicacid tert-butyl ester

The title compound was prepared in analogy to Example 12, from(2-{[4-(2,5-dichloro-phenoxy)-pyridine-3-carbonyl]-amino}-4,5-difluoro-phenyl)-carbamicacid tert-butyl ester and using a gradient of n-heptane:ethyl acetate(100:0 to 0:100) for the chromatographic purification. Colorless foam(63%). MS (ESI): m/z=538.111 [M+H]⁺.

b)(2-{[4-(2,5-Dichloro-phenoxy)-pyridine-3-carbonyl]-amino}-4,5-difluoro-phenyl)-carbamicacid tert-butyl ester

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and(2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester(WO2008000643A1) and using a gradient of n-heptane:ethyl acetate (100:0to 40:60) for the chromatographic purification. Light yellow solid(73%). MS (ESI): m/z=510.080 [M+H]⁺.

Example 224-(2,5-Dichloro-phenoxy)-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and1,2,3,4-tetrahydro-quinolin-8-ylamine (commercially available; CAS RN54012-92-9) and using a gradient of n-heptane:ethyl acetate (100:0 to0:100) for the chromatographic purification. Light yellow solid (88%).MS (ESI): m/z=414.077 [M+H]⁺.

Example 234-(2,5-Dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, from4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-nicotinamideand using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for thechromatographic purification. Colorless oil (67%). MS (ESI): m/z=417.088[M+H]⁺.

Intermediate4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate),3-amino-2-(dimethylamino)pyridine (commercially available, CAS RN5028-25-1) and using a gradient of n-heptane:ethyl acetate (100:0 to0:100) for the chromatographic purification. Light yellow solid (73%).MS (ESI): m/z=403.072 [M+H]⁺.

Example 244-(2,5-Dichloro-phenoxy)-N-methyl-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide

The title compound was prepared in analogy to Example 12, from4-(2,5-dichloro-phenoxy)-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide(Example 22) and using a gradient of n-heptane:ethyl acetate (100:0 to0:100) for the chromatographic purification. Colorless foam (42%). MS(ESI): m/z=428.092 [M+H]⁺.

Example 25N-[4-Chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide

The title compound was prepared in analogy to Example 12, fromN-[4-chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-nicotinamideand using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for thechromatographic purification. Colorless solid (79%). MS (ESI):m/z=496.058 [M+H]⁺.

Intermediates a)N-[4-Chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-nicotinamide

The title compound was prepared in analogy to Example 1, from4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and4-chloro-N2-cyclopropyl-5-fluoro-N2-methyl-benzene-1,2-diamine and usinga gradient of n-heptane:ethyl acetate (100:0 to 30:70) for thechromatographic purification. Colorless solid (70%). MS (ESI):m/z=446.083 [M+H]⁺.

b) 4-Chloro-N2-cyclopropyl-5-fluoro-N2-methyl-benzene-1,2-diamine

To a solution of 400 mg (16.35 mmol)(5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-methyl-amine in 4 mLmethanol was added 40 mg 10% palladium on activated charcoal (Fluka).The reaction mixture was stirred at room temperature under a hydrogenatmosphere of 1.7 bar for two hours. Ethyl acetate (10 mL) was added andthe reaction mixture was filtered over Dicalite® speed plus (Acros) andconcentrated under vacuum. The residue was purified by silica gelchromatography using a MPLC system (CombiFlash Companion, Isco Inc.)eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40) togive 240 mg (68%) of the title compound as a brown liquid. MS (ESI):m/z=215.075 [M+H]⁺.

c) (5-Chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-methyl-amine

To a solution of 500 mg (2.17 mmol)(5-chloro-4-fluoro-2-nitro-phenyl)-cyclopropyl-amine (J. Med. Chem.1992, 35(8), 1385) in 5 mL N,N-dimethylformamide was added 104 mg (2.385mmol) sodium hydride (60% dispersion in mineral oil) and 339 mg (2.385mmol) methyl iodide. The reaction mixture was stirred for 6 hours atroom temperature and then poured on 30 mL 10% aqueous sodium bicarbonatesolution and 30 mL ethyl acetate. The layers were separated and theaqueous layer was extracted a second time with 30 mL ethyl acetate. Theorganic layers were washed with 30 mL brine, dried over magnesiumsulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography using a MPLC system (CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate100:0 to 80:20) to give 433 mg (82%) of the desired compound as a yellowoil. MS (ESI): m/z=245.049 [M+H]⁺.

Example 26[4-(4-Bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

To a suspension of 5.0 g (13.77 mmol)4-(4-bromo-2,5-dichloro-phenoxy)-nicotinic acid in 30 mLN,N-dimethylformamide were added 5.50 g (14.46 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 7.03 mL (41.32 mmol) N,N-diisopropylethylamine. To this brownsolution was added 2.52 g (14.46 mmol)1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediatea), the resulting clear brown solution was stirred at room temperaturefor 17 hours and then poured on 120 mL water and 120 mL ethyl acetate.The resulting mixture was filtered, the filter cake was thoroughlywashed with water and a very small amount of ethyl acetate to give afterdrying 6.55 g (92%) of the title compound as a brown solid. MS (ESI):m/z=520.1 [M+H]⁺.

Intermediate 4-(4-Bromo-2,5-dichloro-phenoxy)-nicotinic acid

To a stirred suspension of 6.0 g (38.08 mmol) 4-chloronicotinic acid(commercially available; CAS RN 10177-29-4) in 200 mL o-xylene wereadded 10.13 g (41.89 mmol) 4-bromo-2,5-dichlorophenol (commerciallyavailable; CAS RN 1940-42-7) and 2.84 g (7.62 mmol)tetrakis-(acetonitrile)-copper hexafluorophosphate (commerciallyavailable; CAS RN 64443-05-6). Then 31.31 g (95.20 mmol) cesiumcarbonate were added and the resulting dark brown suspension as heatedto 120° C. for 16 hours. After cooling to room temperature, the soventwas evaporated, the residue dissolved in 1.25 l water, extracted fourtimes with 250 mL ethyl acetate and filtered. The pH of the greenfiltrate was adjusted to 6 using 25% aqueous hydrochloric acid. Theformed precipitate was filtered off to give a first batch of the desiredcompound. The pH of the filtrate was adjusted to pH 3 using 25% aqueoushydrochloric acid, the suspension stirred for 0.25 hours at roomtemperature and then kept in the fridge for 64 hours. The suspension wasfiltered and washed with water to yield another batch of compound. Brownsolid (overall yield 5.63 g (41%)). MS (ESI): m/z=363.9 [M+H]⁺.

Examples 27 and 282,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid methyl ester and4-Chloro-5-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phthalicacid dimethyl ester

To a solution of 1.0 g (1.93 mmol)[4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanonein 25 mL methanole and 25 mL ethyl acetate were added 0.40 mL (2.89mmol) triethylamine and 0.094 g (0.12 mmol)1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane adduct (commercially available, CAS RN 851232-71-8).Then, a 70 bar carbon monoxide atmosphere was installed and the reactionmixture was stirred at 120° C. for 20 hours. After cooling down, thereaction mixture was filtered and the filtrate was treated with silicagel and evaporated. The resulting powder was then purified by silica gelchromatography using a MPLC system (50 g silica gel column, CombiFlashCompanion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate(100:0 to 50:50) to give a first batch of each compound. The remainingfractions containing impurities were combined and again chromatographed(20 g silica gel column, CombiFlash Companion, Isco Inc.) using agradient of n-heptane:ethyl acetate (100:0 to 40:60) to give a secondbatch of the desired compounds.

2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid methyl ester (Example 27): 0.413 g (43%) light brown foam. MS(ESI): m/z=498.3 [M+H]⁺.

4-Chloro-5-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phthalicacid dimethyl ester (Example 28): 0.278 g (27%) light brown foam. MS(ESI): m/z=522.142 [M+H]⁺.

Example 29{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-aceticacid methyl ester

To a solution of 0.18 g (0.37 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brownsolution 0.049 g (0.39 mmol) glycine methyl ester hydrochloride(commercially available, CAS RN 5680-79-5) was added and the solutionwas stirred at room temperature for 2.5 hours. The solution was pouredon water and extracted three times with ethyl acetate. The combinedorganic layers were washed twice with water and brine, dried overmagnesium sulfate, filtered, treated with silica gel and evaporated. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (10 g silica gel column, CombiFlash Companion, Isco Inc.) with agradient of n-heptane:ethyl acetate (100:0 to 0:100) to yield 0.169 g(82%) of the desired compound as a light brown solid. MS (ESI):m/z=555.12 [M+H]⁺.

Intermediate2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid

To a suspension of 3.68 g (7.38 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid methyl ester (Example 27) in 40 mL dioxane and 40 mL water wereadded 0.387 g (9.22 mmol) lithium hydroxide mono hydrate. The reactionmixture was stirred 1.5 hours at room temperature upon which a yellowsolution formed. Dioxane was removed by evaporation and the resultingsuspension was diluted with 50 mL water and the pH was adjusted to 1using 10 mL 25% aqueous hydrochloric acid. The resulting suspension wasstirred for approx. 2 hours at room temperature, filtered, washed withwater and dried under high vacuum to give 3.49 g (97%) of the desiredcompound as a light brown solid. MS (ESI): m/z=484.3 [M+H]⁺.

Example 30{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-aceticacid

To a suspension of 0.148 g (0.27 mmol){2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-aceticacid methyl ester (Example 29) in 1.5 mL dioxane and 1.5 mL water wasadded 0.014 g (0.33 mmol) lithium hydroxide monohydrate. After 2 hoursstirring at room temperature the organic solvent was evaporated. The pHof the resulting yellow solution was adjusted to 1 with 1M aqueoushydrochloric acid and the solution was extracted three times with ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered and evaporated to give 0.091 g (63%) of thetitle compound as a yellow foam. MS (ESI): m/z=541.104 [M+H]⁺.

Example 31({2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-aceticacid methyl ester

The title compound was prepared in analogy to Example 29, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and sarcosine methylester hydrochloride(commercially available, CAS RN 945218-53-1) and using a gradient ofn-heptane:ethyl acetate (100:0 to 0:100) as eluant. Light brown foam(33%). MS (ESI): m/z=569.135 [M+H]⁺.

Example 32({2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-aceticacid

To a solution of 0.057 g (0.10 mmol)({2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-aceticacid methyl ester (Example 31) in 1 mL dioxane and 1 mL water was added0.005 g (0.12 mmol) lithium hydroxide monohydrate. After stirring atroom temperature for 2 hours, dioxane was removed by evaporation. The pHof the formed yellow solution was adjusted to 1 with 1M aqueoushydrochloric acid. The aqueous solution was saturated with solid sodiumchloride and extracted three times with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered and evaporated to give 0.053 g (95%) of the title compound as ayellow solid. MS (ESI): m/z=555.12 [M+H]⁺.

Example 333-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionicacid ethyl ester

To a solution of 0.18 g (0.37 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added0.148 g (0.39 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brownsolution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride(commercially available, CAS RN 4244-84-2) was added and the solutionwas stirred at room temperature for 3.5 hours. The solution was pouredon water and extracted three times with ethyl acetate. The combinedorganic layers were washed twice with water and brine, dried overmagnesium sulfate, filtered, treated with silica gel and evaporated. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (10 g silica gel column, CombiFlash Companion, Isco Inc.) with agradient of n-heptane:ethyl acetate (100:0 to 0:100) to afford 0.185 g(85%) of the title compound as a light brown foam. MS (ESI): m/z=583.15[M+H]⁺.

Example 343-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionicacid

To a solution of 0.85 g (1.46 mmol)3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionicacid ethyl ester (Example 33) in 7.5 mL dioxane were added 7.5 mL waterand 0.076 g (1.81 mmol) lithium hydroxide monohydrate. The resultingsuspension was stirred for 2.25 hours at room temperature and dioxanewas removed by evaporation. The pH of the solution was adjusted to 2.5by adding 1.9 mL 1M aqueous hydrochloric acid and the suspension wasstirred for 2 hours at room temperature. The suspension was filtered,the filter cake washed with water and dried under high vacuum to give0.70 g (86%) of the desired compound as an off-white solid. MS (ESI):m/z=555.12 [M+H]⁺.

Example 352-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-ethanesulfonicacid

To a solution of 0.127 g (0.26 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) in 1.5 mL N,N-dimethylformamide wereadded 0.10 g (0.26 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 0.13 mL (0.79 mmol) N,N-diisopropylethylamine. To the yellowsolution 0.036 g (0.29 mmol) taurine (commercially available, CAS RN107-35-7) was added and the reaction mixture stirred at room temperaturefor 4.5 hours. The solution was filtered using a syringe micro filterand purified on a preparative HPLC system (Phenomenex Gemini column)with a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2) to give 0.092 g (59%) of the title compound as a brownsolid. MS (ESI): m/z=591.086 [M+H]⁺.

Example 362-({2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoyl}-methyl-amino)-ethanesulfonicacid

The title compound was prepared in analogy to Example 35, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and N-methyl taurine (commerciallyavailable, CAS RN 107-68-6). Brown solid (27%). MS (ESI): m/z=605.2[M+H]⁺.

Example 373-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propane-1-sulfonicacid

The title compound was prepared in analogy to Example 35, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 3-amino-1-propanesulfonic acid(commercially available, CAS RN 3687-18-1). Brown solid (18%). MS (ESI):m/z=605.102 [M+H]⁺.

Example 382,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide

To a solution of 0.20 g (0.41 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added0.165 g (0.43 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 0.21 mL (1.24 mmol) N,N-diisopropylethylamine. To the yellowsolution 0.037 g (0.43 mmol) 5-amino-1H-tetrazole (commerciallyavailable, CAS RN 4418-61-5) was added and the solution was stirred atroom temperature for 3.25 hours. Then the solution was heated to 60° C.and stirred at this temperature for 88 hours. After filtration over asyringe micro filter, the reaction mixture was purified by preparativeHPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water(containing 0.05% formic acid) (10:90 to 98:2) to give the desiredcompound as a light brown solid (0.051 g, 22%). MS (ESI): m/z=551.11[M+H]⁺.

Example 392,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide

The title compound was prepared in analogy to Example 38, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 5-(aminomethyl)-tetrazole(commercially available, CAS RN 31602-63-8) to provide 0.078 g (58%) ofthe title compound as a light yellow solid. MS (ESI): m/z=565.126[M+H]⁺.

Example 404-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-butyricacid

The title compound was prepared in analogy to Example 30, from4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-butyricacid methyl ester. Light brown solid (62%). MS (ESI): m/z=569.136[M+H]⁺.

Intermediate4-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-butyricacid methyl ester

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and methyl 4-aminobutyrate (commerciallyavailable, CAS RN 3251-07-8) and using a gradient of n-heptane:ethylacetate (100:0 to 0:100) for the chromatographic purification. Lightbrown foam (42%). MS (ESI): m/z=583.150 [M+H]⁺.

Example 414-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylicacid methyl ester

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and4-amino-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (commerciallyavailable, CAS RN 180258-45-1) and using a gradient of n-heptane:ethylacetate (100:0 to 0:100) for the chromatiographic purification. Lightbrown foam (70%). MS (ESI): m/z=620.147 [M+H]⁺.

Example 424-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylicacid

To a solution of 0.10 g (0.16 mmol)4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylicacid methyl ester (Example 41) in 1 mL dioxane were added 1 mL water and0.008 g (0.19 mmol) lithiumhydroxide monohydrate. The resultingsuspension was stirred for 2 hours at room temperature, then heated to80° C. for 5.5 hours. Another 0.001 g (0.024 mmol) lithiumhydroxidemonohydrate were added and the reaction mixture was heated for another1.5 hours at 80° C. After stirring at room temperature for 64 hours thereaction mixture was poured on 1M aqueous hydrochloric acid and ethylacetate and the layers were separated. The aqueous layer was extractedthree times with ethyl acetate. The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered and evaporated. Theresidue was dissolved in N,N-dimethylformamide, filtered over a syringemicrofilter and purified by preparative HPLC (Phenomenex Gemini column)with a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2) to give the title compound as a light brown solid (0.034g, 35%). MS (ESI): m/z=606.13 [M+H]⁺.

Example 434-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoicacid methyl ester

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 4-amino-benzoic acid methyl ester(commercially available, CAS RN 619-45-4) and using a gradient ofn-heptane:ethyl acetate (100:0 to 0:100) for the chromatographicpurification. Light brown foam (29%). MS (ESI): m/z=617.136 [M+H]⁺.

Example 444-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoicacid

To a solution of 0.040 g (0.065 mmol)4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoicacid methyl ester (Example 43) in 0.5 mL dioxane were added 0.5 mL waterand 0.003 g (0.071 mmol) lithiumhydroxide monohydrate. The resultingsuspension was stirred at room temperature for 2 h, followed by heatingto 80° C. for 1 hour. The organic solvent was removed by evaporation andthe pH of the resulting solution was adjusted to 1 to 2 using 1M aqueoushydrochloric acid. The suspension was stirred for 2 hours at roomtemperature, filtered and washed with water to yield the desiredcompound as a light brown solid (0.020 g, 51%). MS (ESI): m/z=603.12[M+H]⁺.

Example 452-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (commerciallyavailable, CAS RN 7210-76-6) and using a gradient of n-heptane:ethylacetate (100:0 to 0:100) for the chromatographic purification. Yellowsolid (0.182 g; 67%). MS (ESI): m/z=652.12 [M+H]⁺.

Example 462-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylicacid

To a solution of 0.16 g (0.25 mmol)2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylicacid ethyl ester (Example 45) in 2 mL dioxane were added 2 mL water and0.013 g (0.31 mmol) lithiumhydroxide monohydrate. The resultingsuspension was stirred at room temperature for 2 hours and then stirredat reflux temperature for 5.5 hours. Another 0.013 g (0.31 mmol)lithiumhydroxide monohydrate were added and heating was continued foranother 8 hours. The oil bath was removed and the reaction mixture wasstirred at room temperature overnight. After evaporation of the organicsolvent the pH of the resulting solution was adjusted to 2 to 3 using 1Maqueous hydrochloric acid and the solution was extracted three timeswith ethyl acetate. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered and evaporated. The product waspurified by preparative HPLC (Phenomenex Gemini Column) with a gradientof acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) togive 0.058 g (37%) of the title compound as a light brown solid. MS(ESI): m/z=624.1 [M+H]⁺.

Example 475-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylicacid ethyl ester

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (commerciallyavailable, CAS RN 64837-53-2) and using a gradient of n-heptane:ethylacetate (100:0 to 0:100) for the chromatographic purification. Yellowsolid (67%). MS (ESI): m/z=652.12 [M+H]⁺.

Example 482,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-[1,3,4]thiadiazol-2-yl-benzamide

To a solution of 0.10 g (0.16 mmol)5-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylicacid ethyl ester (Example 47) in 1 mL dioxane were added 1 mL water and0.008 g (0.19 mmol) lithiumhydroxide monohydrate. The resultingsuspension was stirred for 2 hours at room temperature and then at 80°C. for 5.5 hours. Another 0.001 g (0.024 mmol) lithiumhydroxidemonohydrate was added and the reaction mixture was heated for another1.5 hours at 80° C. After stirring at room temperature for 64 hours thereaction mixture was poured on 1M aqueous hydrochloric acid and ethylacetate and the layers were separated. The aqueous layer was extractedthree times with ethyl acetate. The combined organic layers were washedwith brine, dried over magnesium sulfate, filtered and evaporated. Theresidue was dissolved in N,N-dimethylformamide, filtered over a syringemicrofilter and purified by preparative HPLC (Phenomenex Gemini column)with a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2) to give 0.030 g (33%) of the product as a light yellowsolid. MS (ESI): m/z=567.08 [M+H]⁺.

Example 492,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(2-hydroxy-ethyl)-benzamide

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 2-amino-ethanol (commerciallyavailable, CAS RN 141-43-5). The product was purified on a preparativeHPLC system (Phenomenex Gemini column) using a gradient ofacetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) togive the desired compound as a light brown foam (60%). MS (ESI):m/z=527.124 [M+H]⁺.

Example 502,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N,N-bis-(2-hydroxy-ethyl)-benzamide

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 2-(2-hydroxy-ethylamino)-ethanol(commercially available, CAS RN 111-42-2). The product was purified on apreparative HPLC system (Phenomenex Gemini column) using a gradient ofacetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) togive the desired compound as a light brown solid (71%). MS (ESI):m/z=571.150 [M+H]⁺.

Example 512,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-benzamide

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 2-amino-propane-1,3-diol(commercially available, CAS RN 534-03-2). The product was purified on apreparative HPLC system (Phenomenex Gemini column) using a gradient ofacetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) togive the desired compound as a light brown foam (72%). MS (ESI):m/z=559.2 [M+H]⁺.

Example 522,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzamide

To a solution of 0.10 g (0.21 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) in 1 mL N,N-dimethylformamide were added0.022 g (0.41 mmol) ammonium chloride, 0.028 g (0.21 mmol)1-hydroxybenzotriazole, 0.07 mL N,N-diisopropylethylamine and 0.040 g(0.21 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimidehydrochloride. The resulting mixture was stirred at room temperatureovernight, filtered over a syringe micro filter and purified on apreparative HPLC system (Phenomenex Gemini column) using a gradient ofacetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) toafford 80 mg (80%) of the desired compound as a light brown solid. MS(ESI): m/z=483.098 [M+H]⁺.

Example 53N-(2-Carbamoyl-ethyl)-2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzamide

The title compound was prepared in analogy to Example 52, from3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionicacid (Example 34) and 3-amino-propionamide (commercially available, CASRN 4726-85-6). Light brown foam (74%). MS (ESI): m/z=554.136 [M+H]⁺.

Example 544-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-heptanedioicacid dimethyl ester

The title compound was prepared in analogy to Example 1, from2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid (Example 29, intermediate) and 4-amino-heptanedioic acid dimethylester (J. Am. Chem. Soc. 2005, 127 (50), 17877-17887) and using agradient of n-heptane:ethyl acetate (100:0 to 0:100) for thechromatographic purification. Light brown foam (69%). MS (ESI):m/z=669.19 [M+H]⁺.

Example 55(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxymethyl-phenoxy)-pyridin-3-yl]-methanone

To a solution of 0.10 g (0.20 mmol)2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoicacid methyl ester (Example 27) in 1 mL tetrahydrofuran was added 0.008 g(0.21 mmol) lithium aluminium hydride. The resulting suspension wasstirred at room temperature for 2.5 hours, poured on aqueous saturatedsodium bicarbonate solution and extracted three times with ethylacetate. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered, treated with silica gel and evaporated todryness. The resulting powder was purified by silica gel chromatographyusing a MPLC system (10 g silica gel column, CombiFlash Companion, IscoInc.) with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) togive 0.025 g (26%) of the desired compound as a light brown oil. MS(ESI): m/z=470.103 [M+H]⁺.

Example 562,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzonitrile

To a suspension of 0.20 g (0.43 mmol)[4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 26) in 0.2 mL N,N-dimethylformamide was added 0.044 g (0.38mmol) L-proline (commercially available, CAS RN 147-85-3) followed bythe addition of 0.068 g (0.76 mmol) copper(I)cyanide. The resulting darkbrown suspension was stirred at 120° C. for 17 hours. Then another 0.2mL N,N-dimethylformamide were added and stirring was continued foranother 7 hours at 120° C. The reaction was allowed to cool to roomtemperature, stirred for another 64 hours and then partioned betweenwater and ethyl acetate. The resulting turbid mixture was filtered andwashed with ethyl acetate. The layers of the filtrate were separated andthe water layer extracted twice with ethyl acetate. The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand evaporated to dryness. The remaining light brown oil was dissolvedin dichloromethane, treated with silica gel and then evpaorated. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (10 g silica gel column, CombiFlash Companion, Isco Inc.) with agradient of n-heptane:ethyl acetate (100:0 to 40:60) to afford 0.045 g(25%) of the title compound as a brown solid. MS (ESI): m/z=465.1[M+H]⁺.

Example 57(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone

To a solution of 1.0 g (1.93 mmol)[4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 26) in 20 mL dry tetrahydrofuran was added 0.85 mL (3.72 mmol)triisopropylborate (commercially available, CAS RN 5419-55-6). Thesolution was cooled to −75° C. using a dry ice bath and 1.50 mL (2.4mmol) n-butyllithium solution (1.6M in n-hexane) was added over 3 min.to the reaction mixture. Stirring was continued for another 1.5 hours.The dry-ice bath was replaced by an ice bath and 0.98 g (8.17 mmol)acetic acid (50% solution in water) and 0.28 g (2.89 mmol) hydrogenperoxide (35% solution in water) were added. The reaction mixture wasstirred at 0° C. for 1 hour, the cooling batch was removed and stirringwas continued at room temperature for 20 hours. The solution was pouredon 10% aqueous sodium thiosulfate solution and extracted three timeswith ethyl acetate. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered, treated with silica gel andevaporated to dryness. The resulting powder was purified by silica gelchromatography using a MPLC system (20 g silica gel column, CombiFlashCompanion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0to 40:60) to give 0.575 g (65%) of the title compound as a light brownsolid. MS (ESI): m/z=456.2 [M+H]⁺.

Example 58{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-aceticacid ethyl ester

To a solution of 0.15 g (0.33 mmol)(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone(Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol)sodium hydride (60% dispersion in mineral oil, Aldrich, CAS RN7646-69-7). The reaction mixture was stirred for 15 min. at roomtemperature before 0.04 mL (0.36 mmol) ethyl bromoacetate (commerciallyavailable, CAS RN 105-36-2) were added. After stirring at roomtemperature for 3 hours the solution was poured on water and extractedthree times with ethyl acetate. The combined organic layers were washedwith water and brine, dried over magnesium sulfate, filtered, treatedwith silica gel and evaporated. The resulting powder was purified bysilica gel chromatography using a MPLC system (10 g silica gel column,CombiFlash Companion, Isco Inc.) eluting with a gradient ofn-heptane:ethyl acetate (100:0 to 30:70) to give 0.144 g (81%) of thedesired compound as a light yellow foam. MS (ESI): m/z=542.123 [M+H]⁺.

Example 59{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-aceticacid

The title compound was prepared in analogy to Example 30, from{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-aceticacid ethyl ester after a reaction time of 4 hours at room temperatureand stirring of the suspension obtained after acidification for 2 hoursat room temperature. Light brown solid (72%). MS (ESI): m/z=514.092[M+H]⁺.

Example 602-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionicacid ethyl ester

The title compound was prepared in analogy to Example 58, from(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone(Example 57) and 2-bromo-2-methyl-propionic acid ethyl ester(commercially available, CAS RN 600-00-0) after a reaction time of 23hours at room temperature and using a gradient of n-heptane:ethylacetate (100:0 to 40:60) for the chromatographic purification. Lightbrown foam (30%). MS (ESI): m/z=570.156 [M+H]⁺.

Example 612-{2,5-Dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionicacid

The title compound was prepared in analogy to Example 30, from2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionicacid ethyl ester. Light brown solid (61%). MS (ESI): m/z=542.124 [M+H]⁺.

Example 62(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-{4-[2,5-dichloro-4-(2-hydroxy-ethoxy)-phenoxy]-pyridin-3-yl}-methanone

To a solution of 0.15 g (0.33 mmol)(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone(Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol)sodium hydride (60% dispersion in mineral oil, Aldrich). The reactionmixture was stirred for 15 min. at room temperature before 0.03 mL (0.36mmol) 2-bromoethanol (commercially available, CAS RN 540-51-2) wereadded. After stirring for 3 hours at room temperature another 0.03 mL(0.36 mmol) 2-bromoethanole were added. After 72 hours the reactionmixture was poured on water and was extracted three times with ethylacetate. The organic layers were washed with water and brine, dried overmagnesium sulfate, filtered, treated with silica gel and evaporated. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (20 g silica gel column, CombiFlash Companion, Isco Inc.) with agradient of n-heptane:ethyl acetate (100:0 to 25:75) to give 0.075 g(46%) of the title compound as a light brown foam. MS (ESI): m/z=500.113[M+H]⁺.

Example 63(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-methanone

To a solution of 420 mg (1.381 mmol) lithium4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 6 mL dryN,N-dimethylformamide was added 1.17 mL (6.907 mmol)N-ethyldiisopropylamine and 635 mg (1.658 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 289 mg (1.658 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline(Example 8, intermedaite a). The reaction mixture was stirred for 18hours at room temperature and then poured on 30 mL 10% aqueous sodiumbicarbonate solution and 30 mL ethyl acetate. The layers were separatedand the aqueous layer was extracted a second time with 30 mL ethylacetate. The organic layers were washed with 30 mL brine, dried overmagnesium sulfate, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography using a MPLC system (20 gsilica gel column, CombiFlash Companion, Isco Inc.) with gradient ofn-heptane:ethyl acetate (100:0 to 0:100) to give 375 mg (60%) of thetitle compound as a light yellow solid. MS (ESI): m/z=454.108 [M+H]⁺.

Intermediates a) Lithium 4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate

To a solution of 420 mg (1.345 mmol)4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester in 5 mLdioxane was added 5 mL water and 85 mg (2.018 mmol) lithium hydroxidemonohydrate. The reaction mixture was stirred for 2 hours at roomtemperature and then concentrated under vacuum. The so-obtained lightyellow solid was pure enough for the next step without furtherpurification. MS (ESI): m/z=298.004 [M+H]⁺.

b) 4-(2,5-Dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester

To a solution of 0.53 g (2.855 mmol) 4-chloro-6-methyl-nicotinic acidmethyl ester (commercially available, CAS RN 886372-05-0) in 7.5 mL dryN,N-dimethylformamide was added 489 mg (2.998 mmol) 2,5-dichlorophenol,789 mg (5.711 mmol) potassium carbonate, 54 mg (0.286 mmol)copper(I)iodide and 54 mg (0.857 mmol) copper nanopowder (avg. particelsize 100 nm). The reaction mixture was stirred at 120° C. for 3 hoursand then poured on 30 mL 1M aqueous hydrochloric acid and 30 mL ethylacetate. The layers were separated and the aqueous layer was extractedwith 30 mL ethyl acetate. The combined organic layers were washed with30 mL brine, dried over magnesium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gel chromatographyusing a MPLC system (20 g silica gel column, CombiFlash Companion, IscoInc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100), togive 432 mg (48%) of the compound as a light yellow solid. MS (ESI):m/z=312.019 [M+H]⁺.

Example 64[4-(4-Bromo-2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

To a solution of 0.17 g (0.451 mmol)4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid in 3 mL dryN,N-dimethylformamide was added 0.38 mL (2.225 mmol)N-ethyldiisopropylamine and 207 mg (0.541 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 94 mg (0.541 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline(Example 8, intermediate a). The reaction mixture was stirred at roomtemperature for 18 hours and then poured on 30 mL 10% aqueous sodiumbicarbonate solution and 30 mL ethyl acetate. The layers were separated.The aqueous layer was extracted with 30 mL ethyl acetate and thecombined organic layers were washed with 30 mL brine, dried overmagnesium sulfate, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography using a MPLC system (20 gsilica gel column, CombiFlash Companion, Isco Inc.) with a gradient ofn-heptane:ethyl acetate (100:0 to 40:60) to give 55 mg (23%) of thetitle compound as a light yellow solid. MS (ESI): m/z=534.018 [M+H]⁺.

Intermediate a) 4-(4-Bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid

To a solution of 185 mg (0.473 mmol)4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester in3 mL dioxane was added 3 mL water and 30 mg (0.710 mmol) lithiumhydroxide monohydrate. The reaction mixture was stirred for 4 hours atroom temperature, poured on 30 mL 1M aqueous hydrochloric acid and 30 mLdichloromethane and the layers were separated. The aqueous layer wasextracted with 30 mL dichloromethane and the combined organic layerswere washed with 30 mL brine, dried over magnesium sulfate, filtered andconcentrated under vacuum to afford 178 mg (100%) of the title compoundas a colorless solid. MS (ESI): m/z=377.912 [M+H]⁺.

b) 4-(4-Bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester

To a solution of 1.25 g (6.734 mmol) 4-chloro-6-methyl-nicotinic acidmethyl ester (commercially available, CAS RN 886372-05-0) in 30 mLo-xylene was added 1.792 g (7.408 mmol) 4-bromo-2,5-dichlorophenol(commercially available, CAS RN 1940-42-7), 0.502 g (1.347 mmol)tetrakis(acetonitrile)copper (I) hexafluorophosphate (commerciallyavailable, CAS RN 64443-05-6) and 5.536 g (16.836 mmol) cesiumcarbonate. The reaction mixture was stirred at 120° C. for 20 hours andwas then allowed to cool to room temperature. Ethyl acetate (50 mL) andwater (50 mL) was added and stirring was continued for another 10minutes. The reaction mixture was filtered over Dicalite® speed plus(Acros) and the layers were separated. The aqueous layer was extractedwith 200 mL ethyl acetate and the combined organic layers were washedwith 200 mL brine, dried over magnesium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography using a MPLC system (50 g silica gel column, CombiFlashCompanion, Isco Inc.) and a gradient of n-heptane:ethyl acetate (100:0to 40:60) to give 200 mg (8%) of the title compound as a light yellowsolid. MS (Turbo Spray): m/z=391.9 [M+H]⁺.

Example 652,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid methyl ester

To a solution of 0.23 g (0.431 mmol)[4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone(Example 64) in 5 mL methanol and 5 mL ethyl acetate was added 23 mg(0.028 mmol)1,1′-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloridedichloromethane complex (commercially available, CAS RN 851232-71-8) and90 mg (0.647 mmol) triethylamine. The solution was carbonylated withcarbon monoxide at 100° C. at 90 bar. The reaction mixture was purifiedby silica gel chromatography using a MPLC system (CombiFlash Companion,Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to0:100) to give the desired compound as a light yellow solid (142 mg,64.3%). MS (ESI): m/z=512.114 [M+H]⁺.

Example 662,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid

To a solution of 130 mg (0.254 mmol)2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid methyl ester (Example 65) in 2 mL dioxane was added 2 mL water and13 mg (0.317 mmol) lithium hydroxide monohydrate. The reaction mixturewas stirred at room temperature for 4 hours and then poured on 20 mL 1Naqueous hydrochloric acid and 20 mL ethyl acetate The layers wereseparated and the aqueous layer was extracted with 20 mL ethyl acetate.The combined organic layers were washed with 30 mL brine, dried overmagnesium sulfate, filtered and concentrated under vacuum to give 125 mg(98.9%) of the title compound as a light yellow solid. MS (ESI):m/z=498.098 [M+H]⁺.

Example 673-{2,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionicacid ethyl ester

The title compound was prepared in analogy to Example 29, from2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid and beta-alanine ethylester hydrochloride (commercially available,CAS RN 4244-84-2). Colorless foam (73%). MS (ESI): m/z=597.169 [M+H]⁺.

Example 683-{2,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionicacid

To a solution of 83 mg (0.139 mmol)3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionicacid ethyl ester in 2 mL dioxane was added 2 mL water and 7 mg (0.174mmol) lithium hydroxide monohydrate. The reaction mixture was stirredfor 4 hours at room temperature. The reaction mixture was poured on 20mL 1N aqueous hydrochloric acid and 20 mL ethyl acetate and the layerswere separated. The aqueous layer was extracted with 20 mL ethyl acetateand the organic layers were washed with 30 mL brine, dried overmagnesium sulfate, filtered and concentrated under vacuum to give thetitle compound as a light yellow solid (100%). MS (ESI): m/z=569.136[M+H]⁺.

Example 69{2,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-aceticacid methyl ester

The title compound was prepared in analogy to Example 29, from2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid and glycine methyl ester hydrochloride (commercially available, CASRN 5680-79-5). The compound was purified on a preparative HPLC system(Phenomenex Gemini column) with a gradient of acetonitrile:water(containing 0.05% formic acid) (50:50 to 95:5), to give 44 mg (39%) ofthe title compound as a light yellow solid. MS (ESI): m/z=569.136[M+H]⁺.

Example 70{2,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-aceticacid

To a solution of 38 mg (0.067 mmol){2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-aceticacid methyl ester (Example 69) in 2 mL dioxane was added 2 mL water and4 mg (0.083 mmol) lithium hydroxide monohydrate. The reaction mixturewas stirred at room temperature for 4 hours and then poured on 20 mL 1Naqueous hydrochloric acid and 20 mL ethyl acetate. The layers wereseparated and the aqueous layer was extracted a second time with 20 mLethyl acetate. The combined organic layers were washed with 30 mL brine,dried over magnesium sulfate, filtered and concentrated under vacuum toyield 10 mg (27%) of the desired compound as a light yellow solid. MS(ESI): m/z=555.119 [M+H]⁺.

Example 712,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide

The title compound was prepared in analogy to Example 39, from2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid (Example 66) and 5-amino-1H-tetrazole (commercially available, CASRN 4418-61-5). The compound was purified twice by preparative HPLC(Phenomenex Gemini column) with a gradient of acetonitrile:water(containing 0.05% formic acid) (50:50 to 95:5) to give 17 mg (15%) ofthe title compound as a white solid. MS (ESI): m/z=563.109 [M+H]⁺.

Example 722,5-Dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide

The title compound was prepared in analogy to Example 38, from2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid (Example 66) and 5-(aminomethyl)-tetrazole (commercially available,CAS RN 31602-63-8) to provide 47 mg (40%) of the title compound as alight yellow solid. MS (ESI): m/z=579.142 [M+H]⁺.

Example 73[2-Chloro-4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

To a solution of 120 mg (0.355 mmol) lithium2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 3 mL dryN,N-dimethylformamide was added 0.30 mL (1.773 mmol)N-ethyldiisopropylamine and 163 mg (0.425 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 74 mg (0.425 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline(Example 8, intermediate a). The reaction mixture was stirred for 18hours at room temperature and evaporated. The residue was purified on apreparative HPLC system (Phenomenex Gemini column) using a gradient ofacetonitrile:water (containing 0.05% formic acid) (50:50 to 100:0) toprovide 45 mg (26%) of the title compound as a light yellow foam (30%).MS (ESI): m/z=488.07 [M+H]⁺.

Intermediates a) Lithium2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate

To a solution of 130 mg (0.36 mmol)2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid ethyl ester in2 mL dioxane was added 2 mL water and 23 mg (0.541 mmol) lithiumhydroxide monohydrate. The reaction mixture was stirred at 100° C. for 4hours. The reaction mixture was allowed to cool down to room temperatureand was concentrated under high vacuum. The so-obtained light yellowsolid was pure enough for the next step without further purification. MS(ESI): 331.965 [M+H]⁺.

b) 2-Chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid ethyl ester

To a solution of 500 mg (2.136 mmol) ethyl2,4-dichloro-6-methylpyridine-3-carboxylate (commercially available, CASRN 86129-63-7) in 7.5 mL dry N,N-dimethylformamide was added 366 mg(2.243 mmol) 2,5-dichlorophenol and 590 mg (4.272 mmol) potassiumcarbonate and 41 mg (0.214 mmol) copper(I)iodide and 41 mg (0.641 mmol)copper nanopowder (avg. particle size 100 nm). The reaction mixture wasstirred at 120° C. for 18 hours and then poured on 30 ml, 1N aqueoushydrochloric acid and 30 mL ethyl acetate. The layers were separated andthe aqueous layer was extracted a second time with 30 mL ethyl acetate.The combined organic layers were washed with 30 mL brine, dried overmagnesium sulfate, filtered and concentrated under vacuum. The residuewas purified by preparative HPLC (Phenomenex Gemini column) with agradient of acetonitrile:water (50:50 to 100:0) to afford 35 mg (18%) ofthe title compound as a light yellow oil. MS (ESI): 359.995 [M+H]⁺.

Example 74[6-Chloro-4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone

To a solution of 0.12 g (0.29 mmol)[4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone(Example 10) in 1 mL toluene was added 0.11 mL (1.15 mmol) phosphorousoxychloride and the resulting suspension was heated to 100° C. Therapidly formed solution was stirred at this temperature for 2.5 hours,after which another 0.11 mL (1.15 mmol) phosphorous oxychloride wasadded. After stirring for another 2.5 hours the reaction mixture wascooled down to room temperature, poured on saturated aqueous sodiumbicarbonate solution and extracted three times with ethyl acetate. Theorganic layers were washed with brine, dried over magnesium sulfate,filtered, treated with silica gel and evaporated to dryness. Theresulting powder was purified by silica gel chromatography using a MPLCsystem (10 g silica gel column, CombiFlash Companion, Isco Inc.) elutingwith a gradient of n-heptane:ethyl acetate (100:0 to 50:50) yielding alight brown solid containing a mixture of the 2- and4-chloro-substituted compound. The two isomers were separated bypreparative HPLC (Chiralpak AD column) using a mixture of ethanol:n-heptane as eluant (30:70) with the desired product eluting second.White solid (0.026 g, 82%). MS (ESI): m/z=433.03 [M+H]⁺.

Example 75(4-Cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-methanone

To a solution of 230 mg (0.766 mmol)4-(2,5-dichloro-phenoxy)-1-oxy-nicotinic acid in 3 mL dryN,N-dimethylformamide was added 0.65 mL (3.832 mmol)N-ethyldiisopropylamine and 352 mg (0.920 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 160 mg (0.920 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline(Example 8, intermediate a). The reaction mixture was stirred at roomtemperature for 18 hours and then poured on 30 mL 10% aqueous sodiumbicarbonate solution and 30 mL ethyl acetate. The layers were separatedand the aqueous layer was extracted with 30 mL ethyl acetate. Thecombined organic layers were washed with 30 mL brine, dried overmagnesium sulfate, filtered and concentrated under vacuum. The residuewas purified by preparative HPLC (Phenomenex Gemini column) with agradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to98:2). MS (ESI): m/z=456.087 [M+H]⁺.

Intermediate 4-(2,5-Dichloro-phenoxy)-1-oxy-nicotinic acid

To a suspension of 0.5 g (1.760 mmol) 4-(2,5-dichloro-phenoxy)-nicotinicacid (Example 1, intermediate) in 7.5 mL dichloromethane was added 0.542g (2.200 mmol) m-chloroperbenzoic acid (Aldrich, CAS RN 937-14-4) at 0°C. The reaction mixture was stirred for 3 hours at room temperature. Thewhite suspension was filtered and washed with 10 mL dichloromethane togive 492 mg (86%) of the desired compound as a white solid. MS (ESI):m/z=299.983 [M+H]⁺.

Example 76[4-(2,5-Dichloro-phenoxy)-pyrimidin-5-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone

To a solution of 200 mg (0.7 mmol)4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid in 2 mLdichloromethane were added 197 mg (0.77 mmol)2-chloro-1-methylpyridinium iodide (commercially available, CAS RN14338-32-0), 0.2 mL (1.4 mmol) triethylamine and 103 mg (0.77 mmol)1,2,3,4-tetrahydroquinoline (commercially available, CAS RN 635-46-1).The solution was stirred 2 hours at room temperature. The reactionmixture was poured on saturated aqueous sodium bicarbonate solution andextracted three times with dichloromethane. The combined organic layerswere dried over magnesium sulfate and concentrated under vacuum. Theresidue was purified by preparative HPLC (Phenomenex Gemini column)using a gradient of acetonitrile:water (containing 0.05% formic acid)(10:90 to 98:2) to give 5.6 mg (2%) of the desired compound. MS (ESI):m/z=400.2 [M+H]⁺.

Intermediates a) 4-(2,5-Dichloro-phenoxy)-pyrimidine-5-carboxylic acid

To a solution of 515 mg (1.64 mmol)4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid ethyl ester in 10mL tetrahydrofuran/water (2/1 v/v) was added 3.29 mL (3.28 mmol) 1Maqueous sodium hydroxide solution and the resulting solution was heatedby microwave irradiation (Emrys Optimizer, Personal Chemistry) 30minutes at 80° C. Solvents were evaporated under vacuum and the residueextracted three times with ethyl acetate and 1M aqueous hydrochloricacid. The combined organic layers were dried over magnesium sulfate,filtered and evaporated to give 385 mg (57%) of the desired compound asan off-white powder. MS (ESI): m/z=238.8 [M−H]⁻.

b) 4-(2,5-Dichloro-phenoxy)-pyrimidine-5-carboxylic acid ethyl ester

To a solution of 420 mg (2.25 mmol) 4-chloropyrimidine-5-carboxylic acidethyl ester (commercially available, CAS RN 41103-17-7) and 440 mg (2.7mmol) 2,5-dichlorophenol (commercially available, CAS RN 583-78-8) in2.5 mL toluene were added 688 mg (5.17 mmol) cesium carbonate and 168 mg(0.45 mmol) tetrakis(acetonitrile) copper(I) hexafluorophosphate(commercially available, CAS RN 64443-05-6). The reaction was heated toreflux for 2.5 h. The solvent was evaporated and the crude reactionproduct extracted with ethyl acetate from an aqueous saturated solutionof sodium bicarbonate. The organic layer was dried over magnesiumsulfate, filtered and evaporated. The resulting product was purified bysilica gel chromatography using a MPLC system (silica gel column,CombiFlash Companion, Isco Inc.) eluting with a gradient ofn-heptane:ethyl acetate yielding 620 mg (88%) of the desired compound asa light yellow viscous oil. MS (ESI): m/z=313.1 [M+H]⁺.

Example 77[4-(2,5-Dichloro-phenoxy)-pyrimidin-5-yl]-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-methanone

To a solution of 57 mg (0.2 mmol)4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76,intermediate a) in 1.5 mL N,N-dimethylformamide were added 91 mg (0.24mmol) O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluroniumhexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1)and 0.102 mL (0.6 mmol) N,N-diisopropyl-ethylamine. The solution wasstirred 15 minutes at 45° C. followed by addition of 36 mg (0.22 mmol)6-fluoro-1,2,3,4-tetrahydroquinoline (commercially available, CAS RN59611-52-8). The reaction was stirred at 45° C. overnight and purifiedon a preparative HPLC system (Phenomenex Gemini column) using a gradientof acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) togive 2.5 mg (3%) of the desired compound. MS (ESI): m/z=418.1 [M+H]⁺.

Example 78[4-(2,5-Dichloro-phenoxy)-pyrimidin-5-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone

The title compound was prepared in analogy to Example 77, from4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76,intermediate a) and 1,2,3,4-tetrahydroquinoxaline (commerciallyavailable, CAS RN 3476-89-9). The compound was purified by preparativeHPLC (Phenomenex Gemini column) using a gradient of acetonitrile:water(10:90 to 98:2) to give 16 mg (20%) of the desired compound. MS (ESI):m/z=401.0 [M+H]⁺.

Example 79[4-(2,5-Dichloro-phenoxy)-pyrimidin-5-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone

The title compound was prepared in analogy to Example 77, from4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid and1-methyl-1,2,3,4-tetrahydroquinoxaline (commercially available, Metina,catalog number M-636). The compound was purified by preparative HPLC(Phenomenex Gemini column) using a gradient of acetonitrile:water (10:90to 98:2) to give 6.5 mg (8%) of the desired compound. MS (ESI):m/z=415.1 [M+H]⁺.

Example 80 4-(2,5-Dichloro-phenoxy)-pyrimidine-5-carboxylic acid(2-methoxy-pyridin-3-yl)-methyl-amide

To a solution of 50 mg (0.17 mmol)(4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid (Example 76,intermediate a) in 1.5 mL dichloromethane were added 0.05 mL (0.34 mmol)triethylamine and 49 mg (0.19 mmol) 2-chloro-1-methylpyridinium iodide.After stirring at room temperature for 20 minutes, 24 mg (0.19 mmol)2-methoxypyridin-3-amine (commercially available, CAS RN 20265-38-7)were added. After 2 hours, the reaction mixture was poured on water andextracted with dichloromethane. The organic layer was dried overmagnesium sulfate, filtered and evaporated. The crude product wasdissolved in 1 mL N,N-dimethylformamide and 14 mg (0.35 mmol) sodiumhydride (60% suspension in mineral oil) followed by 0.02 mL (0.35 mmol)of methyliodide were added. The reaction was stirred at 50° C. for 2hours. The suspension was filtered using a syringe micro filter andpurified on a preparative HPLC system (Phenomenex Gemini column) using agradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to98:2) to give 28 mg (39%) of the desired compound as a light brownsolid. MS (ESI): m/z=405.0 [M+H]⁺.

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula I 10.0 mg 200.0 mgMicrocrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg FilmCoat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mgTitan dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magesiumstearate and compressed to yield kernels of 120 or350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula I  3.0 mg Polyethylene Glycol 400 150.0 mg AceticAcid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of Polyethylene Glycol400 and water for injection (part). The pH is adjusted to 5.0 by AceticAcid. The volume is adjusted to 1.0 ml by addition of the residualamount of water. The solution is filtered, filled into vials using anappropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula I 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titan dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula I 50.0 mg Lactose, fine powder 1015.0 mgMicrocristalline cellulose (AVICEL PH 102) 1400.0 mg Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mgMagnesiumstearate 10.0 mg Flavoring additives 1.0 mg

The active ingredient is mixed with lactose, microcristalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed withmagnesiumstearate and the flavoring additives and filled into sachets.

1. A compound of formula I,

wherein A¹ is CR¹³ or N; A² is CR¹⁴ or N; R¹ and R² are independentlyfrom each other selected from the group consisting of hydrogen,C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, cyano and C₁₋₇-alkoxy; R¹³ andR¹⁴ are independently from each other selected from the group consistingof hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, cyano,C₁₋₇-alkoxy, amino and C₁₋₇-alkylsulfanyl; R³ is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl,C₁₋₇-alkoxy, cyano, C₃₋₇-cycloalkyl, N-heterocyclyl, five-memberedheteroaryl, phenyl and NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ independently fromeach other are selected from hydrogen, C₁₋₇-alkyl and C₃₋₇-cycloalkyl;R⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,halogen-C₁₋₇-alkyl and C₃₋₇-cycloalkyl; or or R³ and R¹⁴ together are—X—(CR¹⁷R¹⁸)_(n)— and form part of a ring; wherein X is selected fromthe group consisting of —CR¹⁹R²⁰—, O, S, C═O and NR²¹; R¹⁷ and R¹⁸ areindependently from each other hydrogen or C₁₋₇-alkyl; R¹⁹ and R²⁰ areindependently from each other selected from the group consisting ofhydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl, and heterocyclyl optionallysubstituted by one or two groups selected from C₁₋₇-alkyl and halogen,or R¹⁹ and R²⁰ together with the C atom they are attached to form acyclopropyl or oxetanyl ring or together form a ═CH₂ or ═CF₂ group; R²¹is selected from the group consisting of hydrogen, C₁₋₇-alkyl,halogen-C₁₋₇-alkyl, C₃₋₇-cycloalkyl optionally substituted bycarboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl, C₃₋₇-cycloalkyl-C₁₋₇-alkylwherein the C₃₋₇-cycloalkyl is optionally substituted bycarboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl, heterocyclyl,heterocyclyl-C₁₋₇-alkyl, heteroaryl, heteroaryl-C₁₋₇-alkyl,carboxyl-C₁₋₇-alkyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkylcarbonyloxy-C₁₋₇-alkyl, C₁₋₇-alkylsulfonyl, phenyl optionallysubstituted by carboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl,phenylcarbonyl wherein the phenyl is optionally substituted bycarboxyl-C₁₋₇-alkyl or C₁₋₇-alkoxycarbonyl, and phenylsulfonyl whereinthe phenyl is optionally substituted by carboxyl-C₁₋₇-alkyl orC₁₋₇-alkoxycarbonyl, or R²¹ and a R¹⁷ together are —(CH₂)₃— and formpart of a ring, or R²¹ together with a pair of R¹⁷ and R¹⁸ are—CH═CH—CH═ and form part of a ring; and n is 1, 2 or 3; B¹ is N orN⁺—O⁻; B² is CR⁷ or N; R⁵, R⁶ and R⁷ independently from each other areselected from the group consisting of hydrogen, halogen, C₁₋₇-alkyl,C₁₋₇-alkoxy, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy, and cyano; and R⁸,R⁹, R¹⁰, R¹¹ and R¹² are independently from each other selected from thegroup consisting of hydrogen, C₁₋₇-alkyl, C₂₋₇-alkenyl, C₂₋₇-alkinyl,halogen, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen-C₁₋₇-alkoxy, hydroxy,hydroxy-C₁₋₇-alkoxy, hydroxy-C₁₋₇-alkyl, hydroxy-C₃₋₇-alkenyl,hydroxy-C₃₋₇-alkinyl, cyano, carboxyl, C₁₋₇-alkoxycarbonyl,aminocarbonyl, carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl,carboxyl-C₂₋₇-alkinyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkinyl,carboxyl-C₁₋₇-alkoxy, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy,carboxyl-C₁₋₇-alkyl-aminocarbonyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,carboxyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,hydroxy-C₁₋₇-alkyl-aminocarbonyl, di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl, phenyloptionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl or C₁₋₇-alkoxycarbonyl, phenyl-carbonyl whereinthe phenyl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,phenyl-aminocarbonyl wherein the phenyl is optionally substituted by oneto three groups selected from halogen, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, phenyl-C₁₋₇-alkyl wherein the phenyl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-C₂₋₇-alkinyl wherein the phenylis optionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-carbonyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,heteroaryl-aminocarbonyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, and heteroaryl-carbonyl-C₁₋₇-alkylwherein the heteroaryl is optionally substituted by one to three groupsselected from halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl; ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein A¹ is CR¹³, A² is CR¹⁴ and R¹³ and R¹⁴ areindependently from each other selected from the group consisting ofhydrogen, halogen, halogen-C₁₋₇-alkyl and C₁₋₇-alkoxy.
 3. A compoundaccording to claim 1, wherein A¹ is CR¹³, A² is N, and R¹³ is selectedfrom the group consisting of hydrogen, halogen, halogen-C₁₋₇-alkyl andC₁₋₇-alkoxy.
 4. A compound according to claim 1, wherein R¹ and R² areindependently from each other selected from the group consisting ofhydrogen, halogen and halogen-C₁₋₇-alkyl.
 5. A compound according toclaim 1, wherein R³ and R¹⁴ together are —X—(CR¹⁷R¹⁸)_(n)— and form partof a ring; wherein X is —NR²¹—, R²¹ is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl and C₃₋₇-cycloalkyl, R¹⁷ and R¹⁸ areindependently from each other hydrogen or methyl, and n is
 2. 6. Acompound according to claim 1, wherein R³ is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, N-heterocyclyl and—NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶ independently from each other are selectedfrom hydrogen, C₁₋₇-alkyl and C₃₋₇-cycloalkyl, and R⁴ is hydrogen ormethyl.
 7. A compound according to claim 1, wherein B¹ is N or N⁺—O⁻ andB² is CR⁷, with R⁷ being selected from the group consisting of hydrogen,halogen and C₁₋₇-alkyl.
 8. A compound according to claim 1, wherein B¹is N and B² is N.
 9. A compound according to claim 1, wherein R⁵ and R⁶are independently from each other selected from the group consisting ofhydrogen, halogen and C₁₋₇-alkyl.
 10. A compound according to claim 1,wherein at least two of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are selected from thegroup consisting of C₁₋₇-alkyl, C₂₋₇-alkenyl, C₂₋₇-alkinyl, halogen,halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen-C₁₋₇-alkoxy, hydroxy,hydroxy-C₁₋₇-alkoxy, hydroxy-C₁₋₇-alkyl, hydroxy-C₃₋₇-alkenyl,hydroxy-C₃₋₇-alkinyl, cyano, carboxyl, C₁₋₇-alkoxycarbonyl,aminocarbonyl, carboxyl-C₁₋₇-alkyl, carboxyl-C₂₋₇-alkenyl,carboxyl-C₂₋₇-alkinyl, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₂₋₇-alkenyl, C₁₋₇-alkoxycarbonyl-C₂₋₇-alkinyl,carboxyl-C₁₋₇-alkoxy, C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy,carboxyl-C₁₋₇-alkyl-aminocarbonyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,carboxyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl-C₁₋₇-alkyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl-C₁₋₇-alkyl,hydroxy-C₁₋₇-alkyl-aminocarbonyl, di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl, phenyloptionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-carbonyl whereinthe phenyl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,phenyl-aminocarbonyl wherein the phenyl is optionally substituted by oneto three groups selected from halogen, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, phenyl-C₁₋₇-alkyl wherein the phenyl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, phenyl-C₂₋₇-alkinyl wherein the phenylis optionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-carbonyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,heteroaryl-aminocarbonyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, and heteroaryl-carbonyl-C₁₋₇-alkylwherein the heteroaryl is optionally substituted by one to three groupsselected from halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl,and the other ones of R⁸, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.
 11. Acompound according to claim 1, wherein at least two of R⁸, R⁹, R¹⁰, R¹¹and R¹² are selected from the group consisting of halogen, hydroxy,hydroxy-C₁₋₇-alkoxy, hydroxy-C₁₋₇-alkyl, cyano, carboxyl,C₁₋₇-alkoxycarbonyl, aminocarbonyl, carboxyl-C₁₋₇-alkoxy,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkoxy, carboxyl-C₁₋₇-alkyl-aminocarbonyl,carboxyl-C₁₋₇-alkyl-(C₁₋₇-alkylamino)-carbonyl,C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxy-C₁₋₇-alkyl-aminocarbonyl, di-(hydroxy-C₁₋₇-alkyl)aminocarbonyl,aminocarbonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-aminocarbonyl,hydroxysulfonyl-C₁₋₇-alkyl-(C₁₋₇-alkyl-amino)-carbonyl,di-(C₁₋₇-alkoxycarbonyl-C₁₋₇-alkyl)-methylaminocarbonyl,phenyl-aminocarbonyl wherein the phenyl is optionally substituted by oneto three groups selected from halogen, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, heteroaryl-aminocarbonyl wherein the heteroaryl isoptionally substituted by one to three groups selected from halogen,C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkylwherein the heteroaryl is optionally substituted by one to three groupsselected from halogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, carboxyl andC₁₋₇-alkoxycarbonyl, heteroaryl-C₁₋₇-alkyl-aminocarbonyl wherein theheteroaryl is optionally substituted by one to three groups selectedfrom halogen, C₁₋₇-alkoxy, carboxyl and C₁₋₇-alkoxycarbonyl, andheteroaryl-carbonyl-C₁₋₇-alkyl wherein the heteroaryl is optionallysubstituted by one to three groups selected from halogen, C₁₋₇-alkoxy,carboxyl and C₁₋₇-alkoxycarbonyl, and the other ones of R⁸, R⁹, R¹⁰,R¹¹, and R¹² are hydrogen.
 12. A compound according to claim 1, whereinR⁸ and R¹¹ are halogen and R⁹, R¹⁰ and R¹² are hydrogen.
 13. A compoundaccording to claim 1, selected from the group consisting of[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,[4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(6,7-difluoro-3,4-dihydro-2H-quinolin-1-yl)-methanone,[4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,4-(2,5-dichloro-phenoxy)-N-(5-fluoro-2-methoxy-phenyl)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-methyl-N-o-tolyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(2-methoxy-phenyl)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(2-methoxy-pyridin-3-yl)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-phenyl)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-methyl-N-(2-piperidin-1-yl-phenyl)-nicotinamide,N-(3,5-Bis-trifluoromethyl-phenyl)-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(4,5-difluoro-2-methoxy-phenyl)-N-methyl-nicotinamide,N-(5-chloro-2-dimethylamino-phenyl)-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(4,5-difluoro-2-methylamino-phenyl)-N-methyl-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide,4-(2,5-dichloro-phenoxy)-N-(2-dimethylamino-pyridin-3-yl)-N-methyl-nicotinamide,and pharmaceutically-acceptable salts thereof.
 14. A compound accordingto claim 1, selected from the group consisting of4-(2,5-dichloro-phenoxy)-N-methyl-N-(1,2,3,4-tetrahydro-quinolin-8-yl)-nicotinamide,N-[4-chloro-2-(cyclopropyl-methyl-amino)-5-fluoro-phenyl]-4-(2,5-dichloro-phenoxy)-N-methyl-nicotinamide,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide,4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-butyricacid,4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylicacid methyl ester,4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-1-methyl-1H-pyrrole-2-carboxylicacid,4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoicacid methyl ester,4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-benzoicacid,2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylicacid ethyl ester,2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-4-methyl-thiazole-5-carboxylicacid,5-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-[1,3,4]thiadiazole-2-carboxylicacid ethyl ester,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-[1,3,4]thiadiazol-2-yl-benzamide,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(2-hydroxy-ethyl)-benzamide,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N,N-bis-(2-hydroxy-ethyl)-benzamide,and pharmaceutically-acceptable salts thereof.
 15. A compound accordingto claim 1, selected from the group consisting of2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-benzamide,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzamide,N-(2-carbamoyl-ethyl)-2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzamide,4-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-heptanedioicacid dimethyl ester,(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxymethyl-phenoxy)-pyridin-3-yl]-methanone,2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzonitrile,(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone,{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-aceticacid ethyl ester,{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-aceticacid,2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionicacid ethyl ester,2-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-phenoxy}-2-methyl-propionicacid,(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-{4-[2,5-dichloro-4-(2-hydroxy-ethoxy)-phenoxy]-pyridin-3-yl}-methanone,(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-methanone,[4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid methyl ester, and pharmaceutically acceptable salts thereof.
 16. Acompound according to claim 1, selected from the group consisting of2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoicacid,3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionicacid ethyl ester,3-{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-propionicacid,{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-aceticacid methyl ester,{2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoylamino}-aceticacid,2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-yl)-benzamide,2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-N-(1H-tetrazol-5-ylmethyl)-benzamide,[2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,[6-chloro-4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-phenoxy)-1-oxy-pyridin-3-yl]-methanone,[4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone,[4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-methanone,[4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone,[4-(2,5-dichloro-phenoxy)-pyrimidin-5-yl]-(4-methyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone,4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid(2-methoxy-pyridin-3-yl)-methyl-amide, and pharmaceutically acceptablesalts thereof.
 17. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier and/oradjuvant.